Hamilton, Betty K.

Abstract Background: Chronic graft-versus-host disease (cGVHD) is a leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Further investigation is needed to understand cGVHD risk, diagnostic features, and outcomes. Patient-reported outcomes (PROs) are important for characterizing the direct and indirect impact of cGVHD on patients, caregivers, and the healthcare system. THRIVE (NCT05919511) is a prospective, longitudinal observational study of patients at risk for cGVHD to describe the clinical course, burden, and practice patterns for cGVHD. THRIVE uses a novel app-based platform designed for rigorous collection of PROs related to symptoms, quality of life, and indirect costs to the healthcare system. We report preliminary patient demographics and clinical characteristics at study enrollment. Methods: THRIVE includes adults aged ≥18 years in the United States who were enrolled 90–180 days after allo-HCT. Follow-up is for 36 months at intervals determined by clinician standard practice; a virtual site is available for patients who return to community sites for follow-up. Presence or absence of GVHD symptoms, cGVHD therapies when applicable, and adverse events are captured in medical records at clinical visits every ~3 months. In all, 13 PROs are assessed (Cutaneous GVHD Questionnaire [CuGQ], General Anxiety Disorder [GAD-7], Lee Total Symptom Scale [TSS; 7-day], modified Frenchay Activities Index [mFAI], modified Patient-Generated Subjective Global Assessment [mPG-SGA], Oral Health Impact Profile [OHIP-14], Ocular Surface Disease Index [OSDI-12], Patient Health Questionnaire [PHQ-9], Patient-Reported Baseline Data [PRBD], Patient-Reported Caregiver Assessment [PRCA], Patient-Reported Economic, Income, and Insurance Data [PREIID], Patient-Reported Outcomes Measurement Information System–Sexual Function [PROMIS-SF], and Pulmonary GVHD Questionnaire [PulmGQ]). Patients are randomized to sequence groups to complete rotating sets of 4–5 PRO measures via digital platform, monthly (Year 1) then every 2 months (Years 2–3). Recruitment is ongoing (target, 1500 patients). Results: This interim report includes the first 340 patients enrolled in THRIVE (data cutoff: June 17, 2025) at 22 sites across the United States since August 1, 2023. Median (range) age was 60.5 (19–83) years (>70 years, n=60 [18%]). Most patients were male (n=190, 56%), White (n=276, 81%), and had college/graduate education (n=219, 64%). Underlying disease was malignant in 328 (96%) patients; most common malignancies requiring allo-HCT were acute myeloid leukemia (n=129, 38%), myelodysplastic syndrome (n=50, 15%), and acute lymphocytic leukemia (n=37, 11%). Most patients (n=212, 62%) were in complete remission at time of allo-HCT, 282 (83%) enrolled after their first allo-HCT, and median (range) time from allo-HCT to enrollment was 111 (77–211) days. Transplant source was most commonly peripheral blood stem cells (n=272, 80%) from unrelated (n=229, 67%) donors, of whom 169 (50%) were male. Overall, 188 (55%) patients had human leukocyte antigen identical HCT, 72 (21%) had mismatched HCT, and 55 (16%) had haploidentical HCT. Conditioning regimens were myeloablative for 177 (34%) patients, reduced intensity for 164 (48%), and non-myeloablative for 16 (5%). At data cutoff, 296 (87%) patients were continuing in THRIVE; 18/44 (41%) patients who discontinued were alive at discontinuation. There were 107 patients (31%) who developed acute GVHD before enrollment (grade I, n=52; grade II, n=35; grade III, n=9; grade IV, n=0; missing/unknown, n=11); 85 (79%) received systemic treatment for acute GVHD. Overall, 28 (8%) patients had cGVHD at enrollment (mild, n=25; moderate/severe, n=3). Organs affected by cGVHD were skin (n=13), eyes (n=4), and gastrointestinal tract (n=3). Conclusions: THRIVE aims to report on clinical practice for managing risk and treatment of cGVHD after allo-HCT in a prospective cohort of ~1500 patients in the United States for ≤3 years. Although real-world assessment of PROs can be associated with challenges including willingness to participate in an observational study and the collection of data without routine clinical visits, the virtual hybrid design is intended to improve patient access and facilitate data collection. In the 22 months since initiation, 340 patients have been enrolled at 22 sites, and the discontinuation rate is low.

Abstract Background: Dissemination and implementation science (D+I) efforts often begin after clinical trial (CT) efficacy data are available. However, delaying this work limits opportunities to identify barriers and facilitators that can enhance adoption of evidence-based practices. Integrating D+I during trial development, activation, and conduct supports more timely, effective, and scalable implementation. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) includes >125 centers, conducting transplant and cellular therapy (TCT) trials with practice-changing potential, with >17,000 patients enrolled since 2001. Data from Center for International Blood and Marrow Transplant Research (CIBMTR) provides a way to measure real-world adoption. With this comprehensive structure in place, the BMT CTN launched a D+I Committee that established a D+I process to better understand uptake of CT findings and to leverage that information to promote adoption. Methods: Informed by established D+I frameworks, a structured, cyclical process to integrate implementation considerations spanning the CT lifecycle was developed. A multidisciplinary team including experts in D+I, clinicians, and investigators iteratively refined the proposed D+I algorithm. The process begins upstream when a trial concept is approved to move forward, it is shared with the D+I Committee for initial assessment. This includes a landscape review for studies in development using CIBMTR data, literature, and expert experience. The Committee then reviews the developing protocol with the BMT CTN protocol team to proactively identify implementation barriers and facilitators to implementation in real-world settings and outline plans for dissemination. The Committee also provides recommendations for integrating relevant implementation data collection and analyses within the protocol. After study completion, both clinical efficacy and implementation outcomes are analyzed, followed by active dissemination. Additional assessment using surveys, qualitative methods, and CIBMTR data occurs after dissemination to understand adoption. Insights gathered also inform further refinement of the process. Tools and templates are in development to build capacity and ensure consistency for Committee members. Results: To date, the Committee has published three peer-reviewed articles addressing implementation implications of three BMT CTN trials (PMC7735536, PMC8578257, PMC9364468) and a fourth is in press. Using the designed D+I process flow, a current effort used a survey sent to US CIBMTR centers, to evaluate factors influencing the implementation of results of the BMT CTN 1703 trial of post-transplant cyclophosphamide as graft-versus-host disease (GvHD) prophylaxis and assessed dissemination and adoption considerations for the upcoming BMT CTN 2203 CT of ruxolitinib as GvHD prophylaxis. CIBMTR data is being analyzed to demonstrate practice patterns before, during, and after BMT CTN 1703 study completion. This effort has allowed for further refinement of the BMT CTN D+I process flow and has highlighted critical opportunities for incorporating dissemination and implementation objectives and endpoints into BMT CTN protocols. We also used the process to guide a review of severe aplastic anemia treatment gaps and ongoing studies. This review underscored how proactive transplant and non-transplant stakeholder engagement and early implementation planning, core elements of this process, can bridge evidence to practice and advance access to care. A complementary survey on current practice patterns in severe aplastic anemia is ongoing. Conclusions: With the existing structure of the BMT CTN and associated practice registry of the CIBMTR, the BMT CTN D+I Committee developed a systematic process to build D+I considerations into trial workflows to increase real-world impact. This process aims to ensure that barriers to uptake of trial results can be identified and addressed appropriately, improving care quality for patients undergoing TCT.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

Abstract To examine the activity of ibrutinib in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) after the US Food and Drug Administration approval, we conducted a multicenter retrospective study. Data were standardly collected (N = 270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), gastrointestinal (GI) (26%), lung (27%), liver (19%), genital (7%), and others (4.4%). The National Institutes of Health (NIH) severity was mild in 5.7%, moderate 42%, and severe 53%. Thirty-nine percent had overlap subtype. Karnofsky performance status (KPS) was ≥80% in 72%. The median prednisone was 0.21 mg/kg (0-2.27). Ibrutinib was started at a median of 18.2 months after cGVHD onset and in earlier lines of therapy (second line, 26%; third, 30%; fourth, 21%; fifth, 9.6%; sixth, 10%; seventh or higher, 1.2%). Among evaluable patients, the 6-month NIH overall response rate (ORR; complete response [CR]/partial response [PR]) was 45% (PR 42%; CR 3%). The median duration of response was 15 months (range, 1-46). Liver involvement had association with 6-month ORR (multivariate [MVA] odds ratio, 5.49; 95% confidence interval [CI], 2.3-14.2; P < .001). The best overall response was 56%, with most (86%) achieving by 1 to 3 months. With a median follow-up for survivors of 30.5 months, failure-free survival (FFS) was 59% (53%-65%) at 6 months and 41% (36%-48%) at 12 months. On MVA, increased age (hazard ratio [HR], 1.01; 95% CI, 1.0-1.02; P = .033), higher baseline prednisone (HR, 1.92; 95% CI, 1.09-3.38; P = .032), and lung involvement (HR, 1.58; 95% CI, 1.1-2.28; P = .016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.

Abstract The Blood and Marrow Transplant (BMT) Clinical Trials Network conducted a phase 3 randomized trial comparing gilteritinib with placebo after allogeneic hematopoietic cell transplantation (HCT) for FLT3-ITD+ acute myeloid leukemia (AML). The primary analysis demonstrated no statistically significant difference in relapse-free survival (RFS); however, patients with FLT3-ITD measurable residual disease (MRD) peri-HCT had significantly longer RFS with gilteritinib. This analysis investigates the effect of post-HCT gilteritinib vs placebo on health-related quality of life (HRQOL). HRQOL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), FACT-Leukemia (FACT-Leu), and EuroQOL-5 Dimensions (EQ-5D-5L) at post-HCT randomization; day 29; months 3, 6, 12, 18, 24; and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in HRQOL scores at any time point between cohorts. Clinically meaningful and time to improvement in HRQOL were similar in both arms. Despite higher treatment-emergent adverse effects with gilteritinib, response to the question of being “bothered by side effects of treatment” did not differ between groups. Subgroup analysis of MRD-positive and negative patients demonstrated no differences in HRQOL between arms. For patients with FLT3-ITD+ AML undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. This trial was registered at www.ClinicalTrials.gov as #NCT02997202.

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure or immunodeficiency syndromes, it is an intensive treatment and accompanied by short- and long-term physical and psychological symptoms requiring specialized care. With substantial advances in therapeutic approaches for HCT and supportive care, HCT survivors experience less morbidity and mortality. However, disparities in both HCT access and outcomes persist, and HCT survivors and their caregivers often lack access to much-needed psychosocial care. Additionally, more medical and psychosocial resources are needed to holistically care for HCT survivors with chronic graft-versus-host disease (GVHD). Hence, this chapter focuses on three areas pertaining to advances and gaps in HCT care: disparities in access to and outcomes of HCT, psychosocial and physical symptom management with supportive care interventions, and GVHD prevention and management.

Background and Significance: Allogeneic hematopoietic cell transplantation (alloHCT) is a curative immunotherapy for patients with hematologic disorders. However, graft-versus-host-disease (GVHD) is a major limitation to the success of alloHCT, with chronic GVHD (cGVHD) as the leading cause of morbidity and mortality. The pleomorphic nature of cGVHD makes the diagnosis and patient management challenging for clinicians; thus, patient-reported symptoms often guide in diagnosing and determining the severity of cGVHD. Our current understanding of cGVHD is largely based on data from registries, single-institution prospective studies, and the cGVHD Consortium with representation from tertiary care academic centers. Prospective studies including patient-reported outcomes and a focus on a more representative and generalizable sample of patients with cGVHD are needed to better understand cGVHD symptoms, disease burden, and practice patterns for management. This trial in progress focuses on broad patient-centered assessment of post-alloHCT medical and psychosocial complications and patient-reported caregiver involvement in a diverse and contemporary patient population. This study uses multiple organ- or system-directed patient-reported outcome measures (PROMs) to help identify cGVHD symptoms, severity, and impact on patient quality of life including financial impact. The primary objective of THRIVE is to assess the clinical course and burden of cGVHD, including diagnosis and severity recorded in electronic case report forms (eCRFs) and PROMs. Secondary objectives include measuring healthcare resource utilization and patient economic and employment impact associated with cGVHD management, as well as patient-reported organ-specific symptoms. Study Design and Methods: THRIVE is a prospective, longitudinal, observational study (NCT05919511) of alloHCT recipients in the United States that uses a hybrid model designed to work with HCT centers and a virtual platform. Eligible patients are ≥18 years old, received alloHCT 90-180 days before enrollment, and are able to complete patient-assessment questionnaires provided in their preferred language either alone or with minimal caregiver assistance. Up to 1500 alloHCT recipients will be recruited at HCT sites (with the expectation that ~500 will have cGVHD symptoms at enrollment; ~500 are estimated to develop cGVHD during the course of the study; ~500 are estimated not to develop cGVHD during the study; Figure). Patients have the option to participate on a virtual platform. Patients will be followed for 36 months from date of enrollment or until the earliest of study termination, withdrawal, or death. Data from 13 PROMs (Table) divided into 3 groups will be collected every 3 months using a decentralized virtual platform. To reduce survey burden, patients will be randomized into 1 of 6 sequence groups to capture 4-5 PROMs per month in year 1 and every 2 months in years 2 and 3. Clinical data, including medications and adverse events, will be collected and abstracted into eCRFs every 3 months. In general, reporting of results will be descriptive for variables of interest. Summary statistics for continuous variables and for categorical variables will be calculated for all patients as well as for subgroups of interest. Whenever applicable, 95% confidence intervals will be calculated for endpoint estimates. Univariate, multivariate, or repeated-measurement analyses will be performed to assess factors associated with evolution of clinical manifestations of and complications from cGVHD. Recruitment for this study is ongoing.