Treatment responsive acute GVHD after posttransplant cyclophosphamide-based prophylaxis: incidence and clinical outcomes.

BACKGROUND: Post-transplant cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as either corticosteroid-sensitive (SS), dependent (SD), or resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy based prophylaxis. Over one-third of patients developed aGVHD requiring systemic therapy. Cases were predominantly SR with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these three distinct aGVHD treatment response groups following PTCy-based prophylaxis is not well described. OBJECTIVE: The objective of this retrospective, single-institution, cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). STUDY DESIGN: We included 196 consecutive (2017-2021) adult and pediatric patients receiving allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota. Patients received PTCy on days +3 and +4 plus tacrolimus and mycophenolate mofetil prophylaxis. Bone marrow (BM) and peripheral blood stem cell (PBSC) graft sources and related and unrelated donors were included. Recipients received myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens. RESULTS: In 196 allografts, 54 (28%) developed aGVHD before day +180 with median time to onset of 50 days (IQR 34-71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD requiring systemic corticosteroids with the following response: 13 (41%) SS, 10 (31%) SD, and 9 (28%) SR. Overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD while none had grade IV aGVHD. 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), but was lowest in the SR group (20%) with GVHD being the primary cause of death. Non-relapse mortality (NRM) was highest in the SR group. MN high risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. CONCLUSIONS: Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. Acute GVHD cases were predominantly SS aGVHD with a lower incidence of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces rates of treatment resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than SR aGVHD.

Multi-omics analysis of a fecal microbiota transplantation trial identifies novel aspects of acute graft-versus-host disease pathogenesis.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of pre- and post-intervention gut microbiome and serum metabolome. We found that post-intervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g. antibiotics, intestinal damage, alloimmunity) are concurrently in effect.

Body composition and late-occurring chronic health conditions after autologous stem cell transplantation for lymphoma.

BACKGROUND: Autologous peripheral blood stem cell transplantation (aPBSCT) is the standard of care for adults with relapsed lymphoma, yet recipients remain at risk of developing chronic health conditions (CHCs). It was hypothesized that body composition measurements of skeletal muscle and fat are associated with late-onset CHCs and nonrelapse mortality after aPBSCT. METHODS: Leveraging the Blood or Marrow Transplant Survivor Study, we examined association between pre-aPBSCT body composition and new-onset grade 3-5 CHCs among 187 adults with lymphoma treated with aPBSCT (2011-2014) surviving ≥2 years after aPBSCT. Using computed tomography scans at the L3 level, skeletal muscle mass (skeletal muscle area and skeletal muscle density [SMD]) and body fat (subcutaneous adipose tissue and visceral adipose tissue) were measured and quantified as sex-specific z-scores. Competing risk models were built to study the impact of body composition on incident grade 3 through 5 CHCs and nonrelapse mortality (NRM) adjusting for confounders. RESULTS: The study cohort had a median age at aPBSCT of 57 years with 63% males, 77% non-Hispanic Whites and 81% with non-Hodgkin lymphoma. The 5-year cumulative incidence of grade 3 through 5 CHCs was 47% (95% Confidence Interval, CI, 38%-56%). Each SD increase in SMD was associated with 30% reduced risk of grade 3 through 5 CHCs (95% CI, 0.50-0.96). The 10-year cumulative incidence of NRM was 16% (95% CI, 10-22). No body composition measure was associated with NRM. CONCLUSIONS: The association between SMD and grade 3 through 5 CHCs following aPBSCT could inform development of prognostic models to identify adults with lymphoma at greatest risk of morbidity following aPBSCT.

Pre-frailty after blood or marrow transplantation and the risk of subsequent mortality.

We examined the prevalence, risk factors, and association between pre-frailty and subsequent mortality after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 3346 individuals who underwent BMT between 1974 and 2014 at one of three transplant centers and survived ≥2 years post-BMT. Participants completed the BMTSS survey at a median of 9 years from BMT and were followed for subsequent mortality for a median of 5 years after survey completion. Closest-age and same-sex biological siblings also completed the survey. Previously published self-reported indices (exhaustion, weakness, low energy expenditure, slowness, unintentional weight loss) classified participants as non-frail (0-1 indices) or pre-frail (2 indices). National Death Index was used to determine vital status and cause of death. Overall, 626 (18.7%) BMT survivors were pre-frail. BMT survivors had a 3.2-fold higher odds of being pre-frail (95% CI = 1.9-5.3) compared to siblings. Compared to non-frail survivors, pre-frail survivors had higher hazards of all-cause mortality (adjusted hazard ratio [aHR] = 1.6, 95% CI = 1.4-2.0). Female sex, pre-BMT radiation, smoking, lack of exercise, anxiety, and severe/life-threatening chronic health conditions were associated with pre-frailty. The novel association between pre-frailty and subsequent mortality provides evidence for interventions as pre-frail individuals may transition back to their robust state.

Clonal Hematopoiesis and Therapy-Related Myeloid Neoplasms After Autologous Transplant for Hodgkin Lymphoma.

PURPOSE: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell transplantation (aPBSCT) for Hodgkin lymphoma (HL). Although previous studies have reported an association between clonal hematopoiesis (CH) in the infused PBSC product and subsequent post-aPBSCT risk of t-MN in patients with non-HL, information about patients with HL treated with aPBSCT is not available. METHODS: We constructed a retrospective cohort of 321 patients with HL transplanted at a median age of 34 years (range, 18-71). Targeted DNA sequencing of PBSC products performed for CH-associated or myeloid malignancy-associated genes identified pathogenic mutations in these patients. RESULTS: CH was identified in the PBSC product of 46 patients (14.3%) with most prominent representation of DNMT3A (n = 25), PPM1D (n = 7), TET2 (n = 7), and TP53 (n = 5) mutations. Presence of CH in the PBSC product was an independent predictor of t-MN (adjusted hazard ratio [aHR], 4.50 [95% CI, 1.54 to 13.19]). Notably all patients with TP53 mutations in the PBSC product developed t-MN, whereas none of the patients with DNMT3A mutations alone (without co-occurring TP53 or PPM1D mutations) did. Presence of TP53 and/or PPM1D mutations was associated with a 7.29-fold higher hazard of t-MN when compared with individuals carrying no CH mutations (95% CI, 1.72 to 30.94). The presence of TP53 and/or PPM1D mutations was also associated with a 4.17-fold higher hazard of nonrelapse mortality (95% CI, 1.25 to 13.87). There was no association between CH and relapse-related mortality. CONCLUSION: The presence of TP53 and/or PPM1D mutations in the PBSC product increases the risk of post-aPBSCT t-MN and nonrelapse mortality among patients with HL and may support alternative therapeutic strategies.

Amphiregulin, ST2,and REG3α Biomarker Risk Algorithms as Predictors of Non-Relapse Mortality in Patients with Acute GVHD.

Graft-vs-host disease (GVHD) is a major cause of non-relapse mortality (NRM) following allogeneic hematopoietic cell transplant (HCT). Algorithms containing either the GI GVHD biomarker amphiregulin (AREG) or a combination of two GI GVHD biomarkers, (ST2+REG3α) when measured at GVHD diagnosis are validated predictors of NRM risk, but have never been assessed in the same patients using identical statistical methods. We measured serum concentrations of ST2, REG3, and AREG by ELISA at the time of GVHD diagnosis in 715 patients divided by date of transplant into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n=341) was used to develop algorithms for predicting probability of 12 month NRM that contained all possible combinations of 1-3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for risk of NRM. Algorithms were compared to each other based on several metrics including the area under the receiver operating characteristics curve (AUC), proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n=374). All algorithms were strong discriminators of 12 month NRM, whether or not patients were systemically treated (n=321). An algorithm containing only ST2+REG3α had the highest AUC (0.757), correctly classified the most patients (75%), and more accurately risk stratified those who developed Minnesota standard risk GVHD and for patients who received post-transplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk stratified patients with Minnesota high risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

Long- and short-term effects of fecal microbiota transplantation on antibiotic resistance genes: results from a randomized placebo-controlled trial.

In small series, third-party fecal microbiota transplantation (FMT) has been successful in decolonizing the gut from clinically relevant antibiotic resistance genes (ARGs). Less is known about the short- and long-term effects of FMT on larger panels of ARGs. We analyzed 226 pre- and post-treatment stool samples from a randomized placebo-controlled trial of FMT in 100 patients undergoing allogeneic hematopoietic cell transplantation or receiving anti-leukemia induction chemotherapy for 47 ARGs. These patients have heavy antibiotic exposure and a high incidence of colonization with multidrug-resistant organisms. Samples from each patient spanned a period of up to 9 months, allowing us to describe both short- and long-term effects of FMT on ARGs, while the randomized design allowed us to distinguish between spontaneous changes vs. FMT effect. We find an overall bimodal pattern. In the first phase (days to weeks after FMT), low-level transfer of ARGs largely associated with commensal healthy donor microbiota occurs. This phase is followed by long-term resistance to new ARGs as stable communities with colonization resistance are formed after FMT. The clinical implications of these findings are likely context-dependent and require further research. In the setting of cancer and intensive therapy, long-term ARG decolonization could translate into fewer downstream infections.

Treatment-Sensitive and Treatment-Dependent Chronic Graft-versus-Host Disease Yield Superior Failure-Free and Overall Survival Compared to Treatment-Resistant Chronic Graft-versus-Host Disease.

Response to treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment.

Radiation hazards of the Ukraine nuclear power plants: how can international blood and marrow stem cell transplant societies help?

Any conflict in countries that process nuclear power plants raises concerns of the potential radiation injuries to the people in that region and beyond such as the current conflict in Ukraine. International healthcare organizations and societies should prepare for the potential scenarios of nuclear incidents. The Worldwide Network for Blood and Marrow Transplantation (WBMT) and its members, have recent experience preparing for this type of events such as the Fukushima incident in 2011. In this article, we discuss the risks of radiation exposure, current guidelines, and scientific evidence on hematopoietic support, including the role of hematopoietic stem cell transplant (HCT) for those exposed to nuclear radiation, and the role that the WBMT and other global BMT societies can play in triaging and managing people suffering from radiation injuries.

Health care utilization by long-term survivors of blood or marrow transplantation-A Bone Marrow Transplant Survivor Study report.

BACKGROUND: Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated. METHODS: Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. RESULTS: In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. CONCLUSIONS: This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations.

Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial.

PURPOSE: Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute GVHD (aGVHD). In our recent randomized phase II trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against aGVHD. EXPERIMENTAL DESIGN: We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a preplanned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf). RESULTS: dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%; range, 1.6%-74.3%) than those who developed grade II-IV aGVHD (median 25.3%; range, 2.2%-34.8%; P = 0.006). The cumulative incidence of grade II-IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf [14.3% (95% confidence interval, CI, 2.1-37.5) vs. 76.9% (95% CI, 39.7-92.8), P = 0.008]. The only determinant of dMf in cross-validated least absolute shrinkage and selection operator (LASSO)-regularized regression was the patient's pre-FMT microbiota diversity (Pearson correlation coefficient -0.82, P = 1.6 × 10-9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect. CONCLUSIONS: FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.

Amphiregulin as monitoring biomarker for life-threatening acute graft-versushost disease: secondary analysis of two prospective clinical trials.

Not available.

Risky health behaviors and subsequent late mortality after blood or marrow transplantation: a BMTSS report.

We examined the association between risky health behaviors (smoking, heavy alcohol consumption, and lack of vigorous physical activity) and all-cause and cause-specific late mortality after blood or marrow transplantation (BMT) to understand the role played by potentially modifiable risk factors. Study participants were drawn from the BMT Survivor Study (BMTSS) and included patients who received transplantation between 1974 and 2014, had survived ≥2 years after BMT, and were aged ≥18 years at study entry. Survivors provided information on sociodemographic characteristics, chronic health conditions, and health behaviors. National Death Index was used to determine survival and cause of death. Multivariable regression analyses determined the association between risky health behaviors and all-cause mortality (Cox regression) and nonrecurrence-related mortality (NRM; subdistribution hazard regression), after adjusting for relevant sociodemographic, clinical variables and therapeutic exposures. Overall, 3866 participants completed the BMTSS survey and were followed for a median of 5 years to death or 31 December 2021; and 856 participants (22.1%) died after survey completion. Risky health behaviors were associated with increased hazard of all-cause mortality (adjusted hazard ratio [aHR] former smoker, 1.2; aHR current smoker, 1.7; reference, nonsmoker; aHR heavy drinker, 1.4; reference, nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity) and NRM (aHR former smoker, 1.3; aHR current smoker, 1.6; reference, nonsmoker; aHR heavy drinker, 1.4; reference: nonheavy drinker; and aHR no vigorous activity, 1.2; reference, vigorous activity). The association between potentially modifiable risky health behaviors and late mortality offers opportunities for development of interventions to improve both the quality and quantity of life after BMT.

Prediction of Coronary Heart Disease Events in Blood or Marrow Transplantation Recipients.

Background: The long-term risk of coronary heart disease (CHD) and clinical models that predict this risk remain understudied in blood or marrow transplantation (BMT) recipients. Objectives: This study sought to examine the risk of CHD after BMT and identify the associated risk factors. Methods: Participants included patients transplanted between 1974 and 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and those who survived ≥2 years after BMT. Multivariable logistic regression models assessed CHD risk in BMT survivors compared with a sibling cohort. A self-reported questionnaire and medical records provided information regarding sociodemographics, comorbidities, and therapeutic exposures, which were used to develop a CHD risk prediction nomogram. Results: Overall, 6,677 BMT recipients participated; the mean age at BMT was 43.9 ± 17.7 years, 58.3% were male, and 73.3% were non-Hispanic Whites. The median length of follow-up was 6.9 years (range: 2-46.2 years) from BMT. CHD was reported in 249 participants, with a 20-year cumulative incidence of 5.45% ± 0.39%. BMT survivors had a 1.6-fold greater odds of CHD compared with a sibling cohort (95% CI: 1.09-2.40). A nomogram was then developed to predict the risk of CHD at 10 and 20 years after BMT including age at BMT (HR: 1.06/y; 95% CI: 1.04-1.08), male sex (HR: 1.89; 95% CI: 1.15-3.11), a history of smoking (HR: 1.61; 95% CI: 1.01-2.58), diabetes (HR: 2.45; 95% CI: 1.23-4.89), hypertension (HR: 2.02; 95% CI: 1.15-3.54), arrhythmia (HR: 1.90; 95% CI: 0.89-4.06), and pre-BMT chest radiation (yes vs no: HR: 2.83; 95% CI: 1.20-6.67; unknown vs no: HR: 0.88; 95% CI: 0.34-2.28). The C-statistic was 0.77 in the test set (95% CI: 0.70-0.83). Conclusions: This study identified BMT recipients at high risk for CHD, informing targeted screening for early detection and aggressive control of risk factors.

Pre-transplant and longitudinal changes in faecal microbiome characteristics are associated with subsequent development of chronic graft-versus-host disease.

The role of the gastrointestinal microbiome in predisposing to chronic graft-versus-host disease (cGVHD), an immune-mediated haematopoietic cell transplant (HCT) complication, is not well defined. We examined the relationship of the host faecal microbiome with subsequent cGVHD development by analysing baseline stool samples as well as post-HCT changes in microbiome composition and metabolite pathway analyses. We analysed pre-transplant baseline samples from 11 patients who subsequently developed cGVHD compared to 13 controls who did not develop acute GVHD or cGVHD at any time. We found a significant differential abundance of multiple taxa at baseline between cGVHD versus controls, including the Actinobacteria phylum and Clostridium genus. A subgroup analysis of longitudinal samples within each patient revealed a greater loss of alpha diversity from baseline to post-engraftment in patients who subsequently developed cGVHD. Metabolic pathways analysis revealed that two pathways associated with short-chain fatty acid metabolism were enriched in cGVHD patient microbiomes: ß-oxidation and acyl-CoA synthesis, and γ-aminobutyrate shunt. In contrast, a tryptophan catabolism pathway was enriched in controls. Our findings show a distinct pattern of baseline microbiome and metabolic capacity that may play a role in modulating alloreactivity in patients developing cGVHD. These findings support the therapeutic potential of microbiome manipulation for cGVHD prevention.

Phase II, Open-Label Clinical Trial of Urinary-Derived Human Chorionic Gonadotropin/Epidermal Growth Factor for Life-Threatening Acute Graft-versus-Host Disease.

Treatments that aid inflammation resolution, immune tolerance, and epithelial repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening acute graft-versus-host disease (aGVHD). We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF; Pregnyl; Organon, Jersey City, NJ) to standard aGVHD therapy in a prospective Phase II clinical trial (ClinicalTrials.gov identifier NCT02525029). Twenty-two patients with Minnesota (MN) high-risk aGVHD received methylprednisolone 48 mg/m2/day plus 2000 units/m2 of uhCG/EGF s.c. every other day for 1 week. Patients requiring second-line aGVHD therapy received uhCG/EGF 2000 to 5000 units/m2 s.c. every other day for 2 weeks plus standard of care immunosuppression (physician's choice). Responding patients were eligible to receive maintenance doses twice weekly for 5 weeks. Immune cell subsets in peripheral blood were evaluated by mass cytometry and correlated with plasma amphiregulin (AREG) level and response to therapy. Most patients had stage 3-4 lower gastrointestinal tract GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment. The overall proportion of patients with a response at day 28 (primary endpoint) was 68% (57% with complete response, 11% with partial response). Nonresponders had higher baseline counts of KLRG1+ CD8 cells and T cell subsets expressing TIM-3. Plasma AREG levels remained persistently elevated in nonresponders and correlated with AREG expression on peripheral blood T cells and plasmablasts. The addition of uhCG/EGF to standard therapy is a feasible supportive care measure for patients with life-threatening aGVHD. As a commercially available, safe, and inexpensive drug, uhCG/EGF added to standard therapy may reduce morbidity and mortality from severe aGVHD and merits further study.

Phase II Study of Myeloablative 7-8/8-Matched Allotransplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil.

Graft-versus-host disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that a GVHD prophylaxis regimen of post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) would be associated with incidences of acute and chronic GVHD in patients receiving a matched or single antigen mismatched HCT. This Phase II study was conducted at the University of Minnesota using a myeloablative regimen of either total body irradiation (TBI) at a total dose of 1320 cGy, administered in 165-cGy fractions, twice daily from day -4 to day -1, or busulfan (Bu) 3.2 mg/kg daily (cumulative area under the curve, 19,000 to 21,000 µmol/min/L) plus fludarabine (Flu) 40 mg/m2 once daily on days -5 to -2, followed by a GVHD prophylaxis regimen of PTCy 50 mg/kg on days +3 and +4, Tac, and MMF beginning on day +5. The primary endpoint was the cumulative incidence of chronic GVHD necessitating systemic immunosuppression (IST) at 1 year post-transplantation. Between March 2018 and May 2022, we enrolled 125 pediatric and adult patients, with a median follow-up of 813 days. The incidence of chronic GVHD necessitating systemic IST at 1 year was 5.5%. The rate of grade II-IV acute GVHD was 17.1%, and that of grade III-IV acute GVHD was 5.5%. Two-year overall survival was 73.7%, and 2-year graft-versus-host disease-free, relapse-free survival was 52.2%. The 2-year cumulative incidence of nonrelapse mortality was 10.2%, and the rate of relapse was 39.1%. There was no statistically significant difference in survival outcomes between recipients of matched donor transplants versus recipients of 7/8 matched donor transplants. Our data show that myeloablative HCT with PTCy/Tac/MMF results in an extremely low incidence of severe acute and chronic GVHD in well-matched allogeneic HCT.

Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML.

PURPOSE: Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial. METHODS: Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months. RESULTS: In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister. CONCLUSION: In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

Chronic GVHD after steroid-sensitive, -dependent, and -refractory acute GVHD: incidence and clinical outcomes.

Chronic graft-versus-host disease (cGVHD) is a major limitation to the long-term success of allogeneic hematopoietic cell transplantation (HCT). Our prior study of acute GVHD (aGVHD) defined distinct treatment-response groups based on the response to first-line corticosteroids: steroid-sensitive (SS), steroid-resistant (SR), and steroid-dependent (SD) aGVHDs. We conducted a retrospective, single-institution, cohort study to assess the incidence, risk factors, and clinical outcomes of patients with cGVHD after a previous diagnosis of SS, SD, or SR aGVHD, compared with those with no history of aGVHD. Among 784 consecutive adult and pediatric recipients of HCT for hematologic malignancies between 2008 and 2016, 347 (44%) developed aGVHD, with 13% SS, 12% SD, and 19% SR aGVHD. The 3-year cumulative incidence of cGVHD was 25%. Among those with cGVHD, 39% had no prior aGVHD diagnosis, whereas among those with a prior aGVHD diagnosis, 16% had SS, 24% had SD, and 21% had SR aGVHD. Mild or moderate cGVHD was highest among those with preceding SD aGVHD, whereas severe cGVHD was most frequent among those with previous SR aGVHD. We identified SD and SR aGVHDs as significant independent risk factors for the development of cGVHD after allogeneic HCT, whereas SS aGVHD was not a risk factor. Our study demonstrates that cGVHD after SD aGVHD did not have an intermediate prognosis between SR and SS groups as hypothesized; rather, cGVHD after both SD and SR aGVHD have similar prognoses. Our findings suggest that previous aGVHD response states are important predictors of cGVHD severity and outcomes.

How do we improve the translation of new evidence into the practice of hematopoietic cell transplantation and cellular therapy?

The field of hematopoietic cell transplantation and cell therapy (HCT/CT) is advancing rapidly to bring an ever-expanding collection of potentially curative therapies to patients with malignant and non-malignant diseases. The impact of these therapies depends on our ability to implement them as new evidence becomes available to advance the quality of care. There is often a long delay between evidence development and adoption of therapies based on that evidence into clinical practice. In this review, we describe the potential factors based on an implementation framework that could act as facilitators or barriers to adoption of therapies in the context of HCT/CT. We highlight two examples, the first to showcase the efforts to improve the efficiency of adoption of new findings and accelerate improvement in care of HCT/CT patients and the second to discuss the challenges in real world implementation of chimeric antigen receptor T cell therapy. We conclude by reviewing strategies to improve translation of evidence and ways to measure their success.