Treatment-Responsive Acute Graft-versus-Host Disease after Post-Transplantation Cyclophosphamide-Based Prophylaxis: Incidence and Clinical Outcomes.

Post-transplantation 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 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. More than one-third of patients developed aGVHD necessitating systemic therapy. Cases were predominantly SR, with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these 3 distinct aGVHD treatment response groups following PTCy-based prophylaxis have not been well described. 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). We included 196 consecutive adult and pediatric patients undergoing allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2017 and 2021. Patients received PTCy on days +3 and +4 plus tacrolimus and MMF prophylaxis. Bone marrow and peripheral blood stem cell graft sources and related and unrelated donors were included. Recipients received myeloablative or reduced-intensity conditioning regimens. Of the 196 allografts, 54 (28%) developed aGVHD before day +180, with a median time to onset of 50 days (interquartile range, 34 to 71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD necessitating systemic corticosteroids, with the following response: 13 SS (41%), 10 SD (31%), and 9 SR (28%). The overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD, and none had grade IV aGVHD. The 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%), and was lowest in the SR group (20%), with GVHD the primary cause of death. Nonrelapse mortality was highest in the SR group. MN high-risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. aGVHD cases were predominantly SS aGVHD, with lower incidences of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces the rate 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 seen with SR aGVHD.

Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis.

Acute GVHD (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 preintervention and postintervention gut microbiome and serum metabolome. We found that postintervention 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. SIGNIFICANCE: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.

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.

The best GVHD prophylaxis: Or at least progress towards finding it.

Options for GVHD prophylaxis after allogeneic hematopoietic cell transplantation can best be chosen by understanding the pathophysiology of GVHD. Interventions to limit T cell activation, expansion and subsequent tissue injury can each be utilized in designing successful GVHD prevention strategies Depleting, tolerizing or blunting T cells or host antigen presenting cells (APCs), blocking co-stimulation or more broadly suppressing inflammation have all been used. Interventions which spare regulatory T cells (Tregs) may prevent GVHD and facilitate controlled allo-responses and not compromise subsequent relapse risks. Graft manipulations and pharmacologic interventions each have potential to limit the morbidity of GVHD while permitting the immunocompetence to prevent infection or relapse.

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.

Graft-versus-host disease: teaching old drugs new tricks at less cost.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Currently, more patients can receive SCT. This is attributed to the use of reduced intensity regimens and the use of different GVHD prophylaxis that breaks the barrier of human leukocyte antigen, allowing an increase in the donor pool. Once an area with relatively few clinical trial options, there has been an increase in interest in GVHD prophylaxis and treatment, which has led to many US Food and Drug Administration (FDA) approvals. Although there is considerable excitement over novel therapies, many patients may not have access to them due to geographical or other resource constraints. In this review article, we summarize the latest evidence on how we can continue to repurpose drugs for GVHD prophylaxis and treatment. Drugs covered by our review include those that have been FDA approved for other uses for at least 15 years (since 2008); thus, they are likely to have generic equivalents available now or in the near future.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

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.

A prospective phase 2 clinical trial of a C5a complement inhibitor for acute GVHD with lower GI tract involvement.

Involvement of lower gastrointestinal tract (LGI) occurs in 60% of patients with graft-versus-host-disease (GVHD). Complement components C3 and C5 are involved in GVHD pathogenesis. In this phase 2a study, we evaluated the safety and efficacy of ALXN1007, a monoclonal antibody against C5a, in patients with newly diagnosed LGI acute GVHD receiving concomitant corticosteroid. Twenty-five patients were enrolled; one was excluded from the efficacy analysis based upon negative biopsy. Most patients (16/25, 64%) had acute leukemia; 52% (13/25) had an HLA-matched unrelated donor; and 68% (17/25) received myeloablative conditioning. Half the patients (12/24) had a high biomarker profile, Ann Arbor score 3; 42% (10/24) had high-risk GVHD per Minnesota classification. Day-28 overall response was 58% (13/24 complete response, 1/24 partial response), and 63% by Day-56 (all complete responses). Day-28 overall response was 50% (5/10) in Minnesota high-risk and 42% (5/12) in high-risk Ann Arbor patients, increasing to 58% (7/12) by Day-56. Non-relapse mortality at 6-months was 24% (95% CI 11-53). The most common treatment-related adverse event was infection (6/25, 24%). Neither baseline complement levels (except for C5), activity, nor inhibition of C5a with ALXN1007 correlated with GVHD severity or responses. Further studies are needed to evaluate the role of complement inhibition in GVHD treatment.

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.

Patient-Reported Outcomes in Long-Term Survivors of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.

The overall survival in patients with transplantation-eligible multiple myeloma has tripled over the past 2 decades, leading to a growing population of myeloma survivors. However, there is a paucity of data on health-related quality of life (HRQoL), distress, and health behaviors in long-term myeloma survivors who are in stable remission after autologous hematopoietic cell transplantation (AHCT). In this cross-sectional study using data from 2 randomized controlled trials of survivorship care plans and internet-based self-management intervention in transplantation survivors, the primary objective was to measure HRQoL (using the Short Form-12, version 2.0 [SF-12 v2]), distress (using the Cancer- and Treatment-Related Distress [CTXD] instrument), and health behaviors of myeloma survivors in stable remission after AHCT. A total of 345 patients at a median of 4 years (range, 1.4 to 11 years) post-AHCT were included. The mean SF-12 v2 Physical Component Summary (PCS) score was 45.5 ± 10.5, and the mean Mental Component Summary (MCS) score was 51.3 ± 10.1, compared with US population norms of 50 ± 10 for both (P < .001 and P = .021 for PCS and MCS comparisons, respectively). Notably, neither reached the threshold for a minimal clinically important difference. Approximately one-third of the patients had clinically significant distress based on the CTXD total score, with distress reported by 53% of the patients in the Health Burden domain, by 46% in the Uncertainty domain, by 33% in the Finances domain, by 31% in the Family Strain domain, by 21% in the Identity domain, and by 15% in the Medical Demands domain. Preventive care guidelines were adhered to by 81% of the myeloma survivors; however, adherence to exercise and diet guidelines were relatively low, at 33% and 13%, respectively. Myeloma AHCT survivors in stable remission have no clinically meaningful worsening in physical functioning compared with the general population. Survivorship programs should address ongoing distress due to health burden, uncertainty, and finances in myeloma survivors, along with evidence-based targeted interventions for modifiable health behaviors, such as nutrition and exercise.

Human Effectors of Acute and Chronic GVHD Overexpress CD83 and Predict Mortality.

PURPOSE: Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients. EXPERIMENTAL DESIGN: CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined. RESULTS: CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation. CONCLUSIONS: CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.

Bringing Patient and Caregivers Voices to the Clinical Trial Chorus: A Report From the BMT CTN Patient and Caregiver Advocacy Task Force.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.

Cross-sectional study of physical activity among long-term melanoma survivors and population controls.

Physical activity has been associated with improved outcomes among cancer survivors of various malignancies; however, this topic is understudied among melanoma survivors. Our objective was to determine whether long-term melanoma survivors are less likely to meet American Cancer Society physical activity guidelines than non-melanoma population controls. We conducted a cross-sectional survey in 2015 to follow up participants from a case-control study of melanoma and population controls in Minnesota. The primary outcome was meeting American Cancer Society recommendations for healthy physical activity levels. Physical activity, sun protection practices and time spent outside were compared between survivors and controls using generalized linear regression models. Melanoma survivors (N = 724) and controls (N = 639) were similar with the exceptions of daily hours spent outside, sun protection scores, skin tone, and smoking status. Half (50.8%) of melanoma survivors reported meeting the physical activity guidelines, compared to 39.7% of controls (p < 0.0001), with an 11% (95% CI 0.05-0.17) difference after adjusting for potential confounders. While long-term melanoma survivors were more likely to meet American Cancer Society physical activity guidelines than population controls, nearly 50% did not meet recommendations. This finding is concerning given the known improvements in quality of life and survival among physically active cancer survivors. Opportunities remain to promote physical activity among melanoma survivors. Health communications that promote outdoor exercise, in particular, should include advice about sun protection.

Health-Related Quality of Life Outcomes in Older Hematopoietic Cell Transplantation Survivors.

The use of hematopoietic cell transplantation (HCT) has been increasing in older patients. However, the levels if distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors remains largely unknown. In this secondary analysis using data from 2 randomized controlled trials, we analyzed baseline Cancer and Treatment Distress (CTXD) and Confidence In Survivorship Information (CSI) surveys of HCT survivors who were age ≥60 years at the time of transplantation and alive and disease-free ≥1 year post-autologous or -allogeneic HCT. We analyzed associations of these parameters with the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) and a healthcare adherence (HCA) scale, after adjusting for transplantation and patient demographic factors. A total of 567 patients were included. The median patient age at HCT was 65 years, and 68% of the patients underwent autologous HCT. The median CTXD score was .7 (mild), and the greatest distress was reported in the "health burden" subscale. The median CSI score was 1.4 (moderate-high), with the lowest confidence reported in the "late effects" subscale. We found negative Spearman correlations between CTXD score and SF-12 PCS (P = -.59) and MCS (P = -.54) and positive Spearman correlations between CSI score and SF-12 PCS (P = .23) and MCS (P = .30). The median HCA scale score was high at .8. Male sex, autologous HCT, increased distress level, and worse CSI score were associated with lower use of preventive care. Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1 year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

Adult Hematology/Oncology Patient Perspectives on Telemedicine Highlight Areas of Focus for Future Hybrid Care Models.

Introduction: Telemedicine use expanded rapidly during the COVID-19 pandemic, but publications analyzing patient perspectives on telemedicine are few. We aimed to study whether patient perspectives offer insights into how best to utilize telemedicine in the future for hematology and cancer care. Methods: A modified Telemedicine Satisfaction and Usefulness Questionnaire (TSUQ) was sent to adult hematology/oncology outpatients at the University of Minnesota Masonic Cancer Clinic who had ≥1 prior phone and/or video visit between March 15, 2020, and March 31, 2021. Two focus groups were subsequently conducted with volunteers who completed the survey. We evaluated dichotomized TSUQ items using logistic regression, and focus group data were analyzed qualitatively using constant comparison analysis. Results: Of 7,848 invitations, 588 surveys were completed. Focus groups included 16 survey respondents. Most respondents found telemedicine satisfactory, easy to use, and convenient, with the majority preferring a hybrid approach going forward. Oncology patients, females, and higher income earners endorsed decreased telemedicine satisfaction. Concerns were voiced about fewer in-person interactions, communication gaps, and provider style variability. Discussion: Adult hematology/oncology patients had varied perspectives on telemedicine utilization success based on gender, income, and disease burden, suggesting that a one-size-fits-all approach, as was implemented nearly universally during the COVID-19 pandemic, is not an ideal approach for the long term. Given that telemedicine use is likely to remain in some form in most centers, our findings suggest that a nuanced and tailored approach for some patient subgroups and using feedback from patients will make implementation more effective.

Fecal ß-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements.

The intestinal microbiota produces ß-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that ß-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements. We evaluated fecal ß-glucuronidase activity in patients receiving MMF post-allogeneic HCT and post-kidney transplant. Kidney transplant patients had significantly greater ß-glucuronidase activity (8.48 ± 6.21 nmol/hr/g) than HCT patients (3.50 ± 3.29 nmol/hr/g; P = .001). Microbially mediated ß-glucuronidase activity may be a critical determinant in the amount of mycophenolate entering the systemic circulation and an important factor to consider for precision dosing of MMF.

Compilation of longitudinal gut microbiome, serum metabolome, and clinical data in acute myeloid leukemia.

Induction chemotherapy for patients with acute myeloid leukemia (AML) is a unique clinical scenario. These patients spend several weeks in the hospital, receiving multiple antibiotics, experiencing gastrointestinal mucosal damage, and suffering severe impairments in their immune system and nutrition. These factors cause major disruptions to the gut microbiota to a level rarely seen in other clinical conditions. Thus, the study of the gut microbiota in these patients can reveal novel aspects of microbiota-host relationships. When combined with the circulating metabolome, such studies could shed light on gut microbiota contribution to circulating metabolites. Collectively, gut microbiota and circulating metabolome are known to regulate host physiology. We have previously deposited amplicon sequences from 566 fecal samples from 68 AML patients. Here, we provide sample-level details and a link, using de-identified patient IDs, to additional data including serum metabolomics (260 samples from 36 patients) and clinical metadata. The detailed information provided enables comprehensive multi-omics analysis. We validate the technical quality of these data through 3 examples and demonstrate a method for integrated analysis.