HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Phase I/II multisite trial of optimally dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in acute myeloid leukemia.

Clofarabine is an immunosuppressive purine nucleoside analog that may have better anti-leukemic activity than fludarabine. We performed a prospective phase I/II multisite trial of clofarabine with 2 Gy total body irradiation as non-myeloablative conditioning for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia who were unfit for more intense regimens. Our main objective was to improve the 6-month relapse rate following non-myeloablative conditioning, while maintaining historic rates of non-relapse mortality (NRM) and engraftment. Forty-four patients, 53 to 74 (median: 69) years, were treated with clofarabine at 150 to 250 mg/m2 , of whom 36 were treated at the maximum protocol-specified dose. One patient developed multifactorial acute kidney injury and another developed multiorgan failure, but no other grade 3 to 5 non-hematologic toxicities were observed. All patients fully engrafted. The 6-month relapse rate was 16% (95% CI, 5%-27%) among all patients and 14% (95% CI, 3%-26%) among high-risk patients treated at the maximum dose, meeting the pre-specified primary efficacy endpoint. Overall survival was 55% (95% CI, 40%-70%) and leukemia-free survival was 52% (95% CI, 37%-67%) at 2 years. Compared to a historical high-risk cohort treated with the combination of fludarabine at 90 mg/m2 and 2 Gy TBI, protocol patients treated with the clofarabine-TBI regimen had lower rates of overall mortality (HR of 0.50, 95% CI, 0.28-0.91), disease progression or death (HR 0.48, 95% CI, 0.27-0.85), and morphologic relapse (HR 0.30, 95% CI, 0.13-0.69), and comparable NRM (HR 0.85, 95% CI 0.36-2.00). The combination of clofarabine with TBI warrants further investigation in patients with high-risk AML.

Current state of nonengrafting donor leukocyte infusion (focus on microtransplantation for acute myeloid leukemia).

PURPOSE OF REVIEW: Microtransplantation (or micro-stem cell transplantation, MST) is one permutation of alloreactive immunotherapy increasingly studied in clinical trials. It is most commonly applied to patients with myeloid malignancies who are not suitable candidates for allogeneic hematopoietic cell transplantation. This review highlights the past 2 years of work on stem/progenitor cell products in the field of nonengrafting donor leukocyte infusion (NE-DLI), with a focus on applications of MST in acute myeloid leukemia (AML). RECENT FINDINGS: Assessing the utility of MST is hampered by lack of randomized controlled trials and by variability in donor selection algorithms, treatment timing, and unknown factors. The inherent complexity of the bidirectional alloreactive reactions, implicating many cell types, makes it challenging to move beyond correlative, population-level biology toward mechanistic explanations for MST's actions in any given patient-donor pair. Yet there are indicators that by stimulating a recipient-vs.-tumor effect, MST might substantially improve complete remission rates in AML and that it might find a role in postremission therapy. SUMMARY: The mechanistic underpinnings of MST are gradually being disentangled and its clinical development remains in early stages.

Rates and Risk Factors for Post-Traumatic Stress Disorder Symptomatology among Adult Hematopoietic Cell Transplant Recipients and Their Informal Caregivers.

Hematopoietic cell transplant (HCT) can cause significant distress in patients and their informal caregivers. Despite advances in reduced-intensity conditioning and supportive care, few recent studies have reported rates of clinically significant post-traumatic stress disorder (PTSD) symptomatology. Goals of the current study were to examine rates of PTSD and distress in patients and caregivers and to identify sociodemographic and clinical risk factors for PTSD. As part of an annual survivorship survey, 2157 HCT recipients and their caregivers were mailed self-report measures of PTSD and distress. Patients also completed self-report measures of sociodemographic information (eg, age, sex, employment status). Clinical variables (eg, time since transplant, transplant type) were captured in the transplant database. A total of 691 recipients (56% age 60 or above at the time of survey, 47% women, median 10.1 years post-HCT) and 333 caregivers provided PTSD data and were included in the current analyses. More caregivers reported PTSD (6.6%) than patients (3.3%; P = .02). Patients or caregivers who had PTSD reported significantly higher distress related to uncertainty, family strain, medical demands, finances, identity, and health burden (P < .0001) compared with those without PTSD. Patient but not caregiver PTSD was associated with more recent transplant (P = .01 and P = .16, respectively). Rates of PTSD are relatively low in long-term survivors of HCT and their caregivers. Nevertheless, results are consistent with other studies of cancer caregiving suggesting that caregivers often experience greater distress than patients. Timely referral to psychosocial services should be offered to both HCT recipients and caregivers reporting symptoms of PTSD.

A cure-rate model for Q-learning: Estimating an adaptive immunosuppressant treatment strategy for allogeneic hematopoietic cell transplant patients.

Cancers treated by transplantation are often curative, but immunosuppressive drugs are required to prevent and (if needed) to treat graft-versus-host disease. Estimation of an optimal adaptive treatment strategy when treatment at either one of two stages of treatment may lead to a cure has not yet been considered. Using a sample of 9563 patients treated for blood and bone cancers by allogeneic hematopoietic cell transplantation drawn from the Center for Blood and Marrow Transplant Research database, we provide a case study of a novel approach to Q-learning for survival data in the presence of a potentially curative treatment, and demonstrate the results differ substantially from an implementation of Q-learning that fails to account for the cure-rate.

Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients.

Caregivers are critical to recipient recovery after hematopoietic cell transplant (HCT); however, little is known about their long-term health and quality of life (QoL). In this study we surveyed 4446 caregiver-recipient pairs in the post-HCT period to describe their QoL and its determinants. In total, 849 caregiver-recipient pairs at a median of 6 years after autologous or allogeneic HCT responded. Among 849 responding caregivers at a median of 6 years post-HCT, 67% of caregivers were women and 68% indicated they were still providing care to the recipient. Mean and median QoL measures of caregivers were at or above general population norms; however, approximately 20% of caregivers reported poor QoL relative to general population norms. Multivariate analysis revealed that caregiver characteristics, including age, gender, and educational attainment, were important determinants of caregiver QoL. Additional determinants of caregiver QoL included recipient QoL, relapse after autologous HCT, and ongoing use of immunosuppression after allogeneic HCT. Additionally, the prevalence of depression and sleep disorders appear to be higher in caregivers than in the general population. We have identified a population of caregivers who may benefit from interventions aimed at improving QoL and health outcomes. HCT clinical practice should also consider caregiver well-being.

Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease.

Moderate to severe chronic graft-versus-host disease (GVHD) is treated with potent immunosuppressive therapy (IST) to modulate the allo-immune response, control symptoms, and prevent further organ damage. We sought to understand the types of treatments used in clinical practice and the likelihood of successful treatment associated with each. A chart review was performed for 250 adult patients at Fred Hutchinson Cancer Research Center enrolled in a prospective observational study. After a median follow-up of 5.6 years for survivors, approximately one-third were still on IST (of whom half were on fourth or greater line of therapy), one-third were alive and off IST, and one-third had relapsed or died. Approximately half of survivors stopped all IST at least once, although half of these restarted IST after a median of 3.4 months (interquartile range, 2.3 to 8.0) off therapy. Successful discontinuation of IST for at least 9 months was associated with myeloablative conditioning (P = .04), more years since transplant (P = .009), and lack of oral (P < .001) and skin (P = .049) involvement compared with those who had to restart IST. We conclude that patients with chronic GVHD usually receive multiple lines and years of IST, with only a third off IST, alive, and free of malignancy at 5 years after chronic GVHD diagnosis. Patients stopping IST should be cautioned to self-monitor and continue close medical follow-up, especially for 3 to 6 months after stopping IST.

Tools for the Precision Medicine Era: How to Develop Highly Personalized Treatment Recommendations From Cohort and Registry Data Using Q-Learning.

Q-learning is a method of reinforcement learning that employs backwards stagewise estimation to identify sequences of actions that maximize some long-term reward. The method can be applied to sequential multiple-assignment randomized trials to develop personalized adaptive treatment strategies (ATSs)-longitudinal practice guidelines highly tailored to time-varying attributes of individual patients. Sometimes, the basis for choosing which ATSs to include in a sequential multiple-assignment randomized trial (or randomized controlled trial) may be inadequate. Nonrandomized data sources may inform the initial design of ATSs, which could later be prospectively validated. In this paper, we illustrate challenges involved in using nonrandomized data for this purpose with a case study from the Center for International Blood and Marrow Transplant Research registry (1995-2007) aimed at 1) determining whether the sequence of therapeutic classes used in graft-versus-host disease prophylaxis and in refractory graft-versus-host disease is associated with improved survival and 2) identifying donor and patient factors with which to guide individualized immunosuppressant selections over time. We discuss how to communicate the potential benefit derived from following an ATS at the population and subgroup levels and how to evaluate its robustness to modeling assumptions. This worked example may serve as a model for developing ATSs from registries and cohorts in oncology and other fields requiring sequential treatment decisions.

Trans-population graph-based coverage optimization of allogeneic cellular therapy.

Background: Pre-clinical development and in-human trials of 'off-the-shelf' immune effector cell therapy (IECT) are burgeoning. IECT offers many potential advantages over autologous products. The relevant HLA matching criteria vary from product to product and depend on the strategies employed to reduce the risk of GvHD or to improve allo-IEC persistence, as warranted by different clinical indications, disease kinetics, on-target/off-tumor effects, and therapeutic cell type (T cell subtype, NK, etc.). Objective: The optimal choice of candidate donors to maximize target patient population coverage and minimize cost and redundant effort in creating off-the-shelf IECT product banks is still an open problem. We propose here a solution to this problem, and test whether it would be more expensive to recruit additional donors or to prevent class I or class II HLA expression through gene editing. Study design: We developed an optimal coverage problem, combined with a graph-based algorithm to solve the donor selection problem under different, clinically plausible scenarios (having different HLA matching priorities). We then compared the efficiency of different optimization algorithms - a greedy solution, a linear programming (LP) solution, and integer linear programming (ILP) -- as well as random donor selection (average of 5 random trials) to show that an optimization can be performed at the entire population level. Results: The average additional population coverage per donor decrease with the number of donors, and varies with the scenario. The Greedy, LP and ILP algorithms consistently achieve the optimal coverage with far fewer donors than the random choice. In all cases, the number of randomly-selected donors required to achieve a desired coverage increases with increasing population. However, when optimal donors are selected, the number of donors required may counter-intuitively decrease with increasing population size. When comparing recruiting more donors vs gene editing, the latter was generally more expensive. When choosing donors and patients from different populations, the number of random donors required drastically increases, while the number of optimal donors does not change. Random donors fail to cover populations different from their original populations, while a small number of optimal donors from one population can cover a different population. Discussion: Graph-based coverage optimization algorithms can flexibly handle various HLA matching criteria and accommodate additional information such as KIR genotype, when such information becomes routinely available. These algorithms offer a more efficient way to develop off-the-shelf IECT product banks compared to random donor selection and offer some possibility of improved transparency and standardization in product design.

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies.

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n = 1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n = 1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P = .001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n = 21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n = 192; 30%) or exercise (n = 139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

Statistics, philosophy, and health: the SMAC 2021 webconference.

SMAC 2021 was a webconference organized in June 2021. The aim of this conference was to bring together data scientists, (bio)statisticians, philosophers, and any person interested in the questions of causality and Bayesian statistics, ranging from technical to philosophical aspects. This webconference consisted of keynote speakers and contributed speakers, and closed with a round-table organized in an unusual fashion. Indeed, organisers asked world renowned scientists to prepare two videos: a short video presenting a question of interest to them and a longer one presenting their point of view on the question. The first video served as a "teaser" for the conference and the second were presented during the conference as an introduction to the round-table. These videos and this round-table generated original scientific insights and discussion worthy of being shared with the community which we do by means of this paper.

Expert consensus on microtransplant for acute myeloid leukemia in elderly patients -report from the international microtransplant interest group.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Late Effects of Severe Acute Graft-versus-Host Disease on Quality of Life, Medical Comorbidities, and Survival.

Grade III-IV acute graft-versus-host disease (aGVHD) is associated with high short-term morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). The long-term effects after recovery from grade III-IV aGVHD are unknown. This study aimed to analyze late medical comorbidities, quality of life, nonrelapse mortality, and survival in patients treated for grade III-IV aGVHD. Chart review identified late effects, and patients were asked to complete annual surveys to collect patient-reported outcomes. Outcomes were compared between patients with grade 0-I aGVHD and grade III-IV aGVHD who underwent HCT between 2001 and 2019 and survived for at least 1 year post-transplantation. Patients with a history of grade III-IV aGVHD (n = 192) had significantly higher rates of late medical comorbidities (P < .001) and worse physical (P = .01) and mental (P = .04) functioning compared with patients with grade 0-I aGVHD (n = 615). Patients who survived for >1 year post-transplantation and had prior grade III-IV aGVHD also had worse 5-year overall survival (77.5% versus 83.6%; P = .006) and higher nonrelapse mortality (19.2% versus 10.6%; P < .001) compared with those with a history of grade 0-I aGVHD. No between-group difference was found in cumulative incidence of chronic GVHD. Patients who recover from severe aGVHD remain vulnerable to developing late comorbidities. These patients would likely benefit from continued monitoring and supportive care in an attempt to prevent late effects and improve survival.

Long-term patient-reported neurocognitive outcomes in adult survivors of hematopoietic cell transplant.

Survivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively affect quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21 years at HCT and alive ≥2 years following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n = 1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2 years (interquartile range [IQR], 56.8-70.5) and a median 12.0 years (IQR, 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4% to 31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all P < .01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.46-3.10) and sleep impairment (OR, 4.41; 95% CI, 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

Neuropathy and Muscle Cramps in Autologous and Allogeneic Hematopoietic Cell Transplantation Survivors.

Although autologous and allogeneic hematopoietic cell transplantation are used to treat hematologic diseases, they are associated with high morbidity and mortality. The goal of this cross-sectional study was to describe the incidence, characteristics, severity and clinical correlates of neuropathy and muscle cramps, as self-reported by hematopoietic cell transplantation survivors. We included all respondents to a survey conducted July 1, 2020, to June 30, 2021. Surveys were completed online or on-paper according to participants' preferences; they received one reminder if no survey was received 1 month after distribution. Statistics are primarily descriptive comparing subgroups of patients. Of 4641 potentially eligible patients, 1745 responded and are included in the analysis. Participants (615 [35%] autologous, 1130 [65%] allogeneic) were a median age of 64.1 years (interquartile range [IQR] 55.2-70.8) and surveyed at a median of 11 years (IQR 4-21) after their most recent transplantation. Neuropathy symptoms were reported by 65% of autologous recipients, 66% of allogeneic transplant recipients with current chronic graft versus host disease (GVHD), and 45% of allogeneic recipients who never developed chronic GVHD. Muscle cramps were reported by 56% of autologous recipients, and 52% of allogeneic recipients and were rated as "very painful" by nearly half of patients who experienced them. These results suggest that neuropathy symptoms and muscle cramps are much more prevalent among survivors after hematopoietic cell transplantation than previously recognized. Better approaches for prevention and treatment of these bothersome complications are needed.

Outcomes after hematopoietic cell transplantation among non-English- compared to English-speaking recipients.

Multiple studies have documented that racial/ethnic minority patients are less likely to undergo hematopoietic cell transplantation (HCT) in the United States (US), and if they do, they often have worse outcomes. No studies to our knowledge have compared the outcomes of English-speakers to non-English speakers undergoing HCT in the US. To test our hypothesis that non-English speakers have worse outcomes than English speakers after HCT, all transplants performed between 2015 and 2019 at Fred Hutchinson Cancer Research Center in Seattle, WA, USA were analyzed. Cox proportional hazards models were used to test our hypothesis, adjusting for significant clinical covariates. Out of 2051 patients, 106 (5%) were documented to be non-English speakers. Mortality for non-English speakers was not different than English speakers (adjusted HR 1.02, 95% CI 0.63-1.63, p = 0.95). When the analysis was limited to the allogeneic population, the results were similar to the total population (adjusted HR 1.10, 0.64-1.88, p = 0.73). The risk of grade II-IV acute graft-versus-host disease (GVHD) was higher in the non-English speaking subset: adjusted OR 2.01, 95% CI, 1.02-3.98, p = 0.04. These data suggest that non-English speakers have similar survival compared to English speakers following HCT although they have more acute GVHD.

Humoral and Cellular Immune Response to Covid-19 Vaccination in Patients with Chronic Graft-versus-Host Disease on Immunosuppression.

Chronic graft-versus-host disease (cGVHD) and its management with immunosuppressive therapies increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as progression to severe Coronavirus 19 disease (COVID-19). Vaccination against COVID-19 is strongly recommended, but efficacy data are limited in this patient population. In this study, responses to COVID-19 vaccination were measured at 3 time points-after the initial vaccine series, before the third dose, and after the third dose-in adults with cGVHD receiving immunosuppressive therapy. Humoral response was measured by quantitative anti-spike antibody and neutralizing antibody levels. Anti-nucleocapsid antibody levels were measured to detect natural infection. T cell response was evaluated by a novel immunosequencing technique combined with immune repertoire profiling from cryopreserved peripheral blood mononuclear cell samples. Present or absent T cell responses were determined by the relative proportion of unique SARS-CoV-2-associated T cell receptor sequences ("breadth") plus clonal expansion of the response ("depth") compared with those in a reference population. Based on both neutralizing antibody and T cell responses, patients were categorized as vaccine responders (both detected), nonresponders (neither detected), or mixed (one but not both detected). Thirty-two patients were enrolled for the initial series, including 17 (53%) positive responders, 7 (22%) mixed responders, and 8 (25%) nonresponders. All but one patient categorized as mixed responders had humoral responses while lacking T cell responses. No statistical differences were observed in patient characteristics among the 3 groups of patients categorized by immune response, although sample sizes were limited. Significant positive correlations were observed between the robustness of cellular and humoral responses after the initial series. Among the 20 patients with paired samples (pre- and post-third dose), a third vaccination resulted in increased neutralizing antibody titers. cGVHD worsened in 10 patients (26%; 6 after the initial series and 4 after the third dose), necessitating escalation of immunosuppressive doses in 5 patients, although 4 had been tapering immunosuppression and 5 had already worsening cGVHD at the time of vaccination, and a clear association between COVID-19 vaccination and cGVHD could not be drawn. Among the patients with cGVHD on immunosuppressive therapy, 72% demonstrated a neutralizing antibody response after a 2-dose primary COVID-19 vaccination, two-thirds of whom also developed a T cell response; 25% had neither a humoral nor a T cell response. A third dose further amplified the antibody response.

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease.

PURPOSE: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS: One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION: Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.