ABSTRACT
Since 2005 there has been steady decline in chronic graft-versus-host disease (cGVHD) at Fred Hutchinson Cancer Center (FHCC). To better understand this phenomenon, we studied the risk of cGVHD requiring systemic immunosuppression (cGVHD-IS) as a function of hematopoietic cell transplantation (HCT)-date in 3066 survivors from 2005 through 2019. Cox regression models were fit to assess associations of HCT-date (as a continuous linear variable) with cause-specific hazards of cGVHD, using unadjusted and adjusted models. Median follow-up for study subjects was 7.0 years (range, 1.0-17.2). Two-year probabilities of cGVHD-IS declined among all survivors from 45-52% (2005-2007) to approximately 40% (2008-2012) and then further to ~26% by 2017. A decline was also observed when the analysis was restricted to 502 pediatric survivors, with cGVHD-IS probabilities being <10% since 2013. Among 305 adult and pediatric survivors who were transplanted for nonmalignant diseases, cGVHD rates showed greater fluctuation but remained <20% after 2016. Each 5-year increase in HCT-date was associated with a 27% decrease in the cause-specific hazard of cGVHD (unadjusted hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.68-0.78, p<.0001); the HR was 0.81 (95% CI 0.75-0.87, p<.0001) even after adjusting for various factors (age, donor/stem-cell source, race, sex, conditioning intensity, GVHD prophylaxis, among others) that could lead to cGVHD reduction. The decline in cGVHD was not fully explained by demographic shifts and greater use of HCT approaches generally associated with lower cGVHD rates. This observation underscores that single-cohort cGVHD-prevention studies should use contemporaneous and not historical controls for comparisons.
ABSTRACT
Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations.
ABSTRACT
BACKGROUND: Chronic graft-versus-host disease (GVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying response to treatment. The goal of the Predicting the Quality of Response to Specific Treatments (PQRST) in chronic GVHD study is to identify predictors of treatment response. This report describing the study design seeks to raise awareness and invite collaborations with investigators who wish to access clinical data and research samples from this study. METHODS: This is a prospective, observational cohort study involving data collection from patients who are beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. Evaluable participants will have baseline assessments and research samples prior to starting the index therapy, and 1 month after starting treatment. Response assessments occur at 3 and 6 months after start of treatment, or if a new systemic therapy is started before 6 months. Target enrollment is approximately 200 patients at 8 institutions, with at least 6 months of follow up to determine response to index therapy. RESULTS: Enrollment started in July 2020 and was delayed due to the COVID-19 pandemic; as of 3/1/2024, 137 evaluable participants have been enrolled. DISCUSSION: The Chronic GVHD Consortium "PQRST" is a large longitudinal cohort study that aims to investigate predictors of treatment response by identifying biologically and clinically defined patient subgroups. We welcome investigators to collaborate in the use of these data. TRIAL REGISTRATION: NCT04431479.
ABSTRACT
ABSTRACT: Cutaneous sclerosis, a highly morbid subtype of chronic graft-versus-host disease (GVHD), demonstrates limited treatment response under current National Institutes of Health (NIH) response measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs rituximab and a consortium observational study. The validation cohort was a different consortium observational study. Clinician-reported measures (baseline and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 patients were included (training 183 and validation 164). Although multiple skin and joint measures were associated with clinician-reported response on univariate analysis, patient range of motion (PROM) total score, PROM total score change, and NIH 0 to 3 skin change were retained in the final multivariate model (area under the receiver operating characteristic curve [AUC], 0.83 training and 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the human activity profile adjusted activity score (AAS), 36 item short form health survey (SF36) vitality change, Lee symptom scale (LSS) skin, and LSS skin change in the model (AUC, 0.86 training and 0.75 validation). We identified which sclerosis measures have the greatest association with 6-month clinician- and patient-reported treatment responses, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Graft vs Host Disease/diagnosis , Female , Male , Middle Aged , Adult , Transplantation, Homologous , Treatment Outcome , SclerosisABSTRACT
Chronic graft-versus-host disease (GVHD) is an immune-mediated disorder that causes significant late morbidity and mortality following allogeneic hematopoietic cell transplantation. The "Close Assessment and Testing for Chronic GVHD (CATCH)" study is a multi-center Chronic GVHD Consortium prospective, longitudinal cohort study designed to enroll patients before hematopoietic cell transplantation and follow them closely to capture the development of chronic GVHD and to identify clinical and biologic biomarkers of chronic GVHD onset. Data are collected pre-transplant and every two months through one-year post-transplant with chart review thereafter. Evaluations include clinician assessment of chronic GVHD and its manifestations, patient-reported outcomes, multiple biospecimens (blood, saliva, tears, buccal mucosa and fecal samples, biopsies of skin and mouth), laboratory testing, and medical record abstraction. This report describes the rationale, design, and methods of the CATCH study, and invites collaboration with other investigators to leverage this resource. trial registration: This study is registered at www.clinicaltrials.gov as NCT04188912.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adult , Female , Humans , Male , Middle Aged , Biomarkers , Chronic Disease , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Longitudinal Studies , Prospective Studies , Transplantation, Homologous , Multicenter Studies as TopicABSTRACT
Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.
Subject(s)
Immunotherapy, Adoptive , Multiple Myeloma , Multiple Myeloma/therapy , Humans , Cross-Sectional Studies , Surveys and Questionnaires , Receptors, Chimeric Antigen/therapeutic use , Male , Practice Patterns, Physicians'/statistics & numerical data , Practice Guidelines as Topic , Recurrence , FemaleABSTRACT
While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW). We conducted a survey of 1- to 5-yr post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions. Survivors aged 18 to 65 yrs (n = 994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors. Three hundred forty-four (35%) survivors with a mean age of 53 yrs completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic versus autologous HCT (P = .006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (>once a month) (P = .070) and having a more supportive employer (P = .036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions. To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available in Open Access and can be used as a tool to counsel and support these patients.
Subject(s)
Hematopoietic Stem Cell Transplantation , Quality of Life , Return to Work , Survivors , Humans , Hematopoietic Stem Cell Transplantation/psychology , Middle Aged , Adult , Male , Female , Return to Work/statistics & numerical data , Aged , Quality of Life/psychology , Survivors/psychology , Adolescent , Surveys and Questionnaires , Young AdultABSTRACT
Acute encephalopathy, manifesting clinically as delirium, is a common but often unrecognized complication of hematopoietic cell transplantation (HCT). Delirium can occur in patients of any age and is observed after autologous or allogeneic HCT. Although delirium has been studied primarily during initial HCT hospitalizations in recipients of myeloablative conditioning, recent investigations have identified delirium later post-transplantation and in recipients of reduced-intensity conditioning. Acute encephalopathy can be driven by infectious complications, medications, tissue damage, and/or organ dysfunction. Altered consciousness, either mild or profound, is often its only clinical manifestation. Identifying delirium is essential to overall HCT care, because patients who experience delirium have longer hospitalization and recovery times and are at risk for other poor post-HCT outcomes. Given the critical nature of this common complication and the ongoing expansion of HCT for more vulnerable populations, the American Society of Transplantation and Cellular Therapy (ASTCT) recommends intensifying research into post-HCT cognitive changes and establishing standardized definitions that encompass the full spectrum of altered consciousness for clinical care purposes and to provide benchmark endpoints for future research studies. To capture a range of acute neurocognitive changes specifically found in HCT patients (often referred to as acute encephalopathy), the ASTCT proposes a new diagnosis, transplantation-associated altered mentation and encephalopathy (TAME). The TAME diagnosis includes HCT patients who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for delirium and those with acute neurocognitive changes who do not meet all the DSM-5 criteria for delirium (subsyndromal delirium). Early TAME is defined as occurring during conditioning or ≤100 days post-HCT, whereas late TAME occurs >100 days post-HCT in patients with additional HCT-related complications. This manuscript establishes clear diagnostic criteria and discusses factors that can potentially impact the development of TAME, as well as the workup and management of TAME.
Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Brain Diseases/diagnosis , Brain Diseases/therapy , Delirium/diagnosis , Delirium/etiology , Delirium/classification , Delirium/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning/adverse effectsSubject(s)
Cytomegalovirus Infections , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Mycophenolic Acid , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy , Mycophenolic Acid/therapeutic use , Mycophenolic Acid/adverse effects , Mycophenolic Acid/administration & dosage , Cytomegalovirus Infections/mortality , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/complications , Male , Female , Middle Aged , Cytomegalovirus , Adult , Aged , Immunosuppressive Agents/therapeutic useABSTRACT
Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.
Subject(s)
Graft Rejection , Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/methods , Allografts , Male , Female , Adult , Transplantation Chimera , Transplantation, Homologous/methodsABSTRACT
BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized. PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) ≥1x weekly or ≥1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS). RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS ≤ 80. CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.
Subject(s)
Multiple Myeloma , Quality of Life , Humans , Multiple Myeloma/drug therapy , Male , Female , Middle Aged , Cross-Sectional Studies , Aged , AdultABSTRACT
To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.
Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , United States , Cross-Sectional Studies , Female , Male , Child , Surveys and Questionnaires , Schools , AdolescentABSTRACT
As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.
Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Graft vs Host Disease/prevention & control , Graft vs Host Disease/etiology , Survivors , Adult , Practice Guidelines as Topic , Male , ChildABSTRACT
As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the number of HCTs performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pretransplantation, peritransplantation, and post-transplantation exposures and other underlying risk factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and then updated in 2012. An international group of experts was convened to review the contemporary literature and update the recommendations while considering the changing practices of HCT and cellular therapy. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed, but cGVHD management is not covered in detail. These guidelines emphasize the special needs of patients with distinct underlying HCT indications or comorbidities (eg, hemoglobinopathies, older adults) but do not replace more detailed group-, disease-, or condition-specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.
Subject(s)
Hematopoietic Stem Cell Transplantation , Survivors , Humans , Hematopoietic Stem Cell Transplantation/methods , Risk Factors , Survival , SurvivorshipABSTRACT
ABSTRACT: Pediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and â¼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population.
Subject(s)
Hematopoietic Stem Cell Transplantation , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Humans , Child , Influenza, Human/prevention & control , Transplant Recipients , Immunogenicity, Vaccine , Influenza A Virus, H3N2 Subtype , Leukocytes, MononuclearABSTRACT
The use of reduced-intensity conditioning (RIC) regimens has increased in an effort to minimize hematopoietic stem cell transplantation (HCT) end-organ toxicity, including gonadal toxicity. We aimed to describe the incidence of fertility potential and gonadal function impairment in adolescent and young adult survivors of HCT and to identify risk factors (including conditioning intensity) for impairment. We performed a multi-institutional, international retrospective cohort study of patients age 10 to 40 years who underwent first allogeneic HCT before December 1, 2019, and who were alive, in remission, and available for follow-up at 1 to 2 years post-HCT. For females, an AMH level of ≥.5 ng/mL defined preserved fertility potential; an AMH level of ≥.03 ng/mL was considered detectable. Gonadal failure was defined for females as an elevated follicle-stimulating hormone (FSH) level >30 mIU/mL with an estradiol (E2) level <17 pg/mL or current use of hormone replacement therapy (regardless of specific indication or intent). For males, gonadal failure was defined as an FSH level >10.4 mIU/mL or current use of hormone replacement therapy. A total of 326 patients (147 females) were available for analysis from 17 programs (13 pediatric, 4 adult). At 1 to 2 years post-HCT, 114 females (77.6%) had available FSH and E2 levels and 71 (48.3%) had available AMH levels. FSH levels were reported for 125 males (69.8%). Nearly all female HCT recipients had very low levels of AMH. One of 45 (2.2%) recipients of myeloablative conditioning (MAC) and four of 26 (15.4%) recipients of reduced-intensity conditioning (RIC) (P = .06) had an AMH ≥.5 ng/m, and 8 of 45 MAC recipients (17.8%) and 12 of 26 RIC recipients (46.2%) (P = .015) had a detectable AMH level. Total body irradiation (TBI) dose and cyclophosphamide equivalent dose (CED) were not associated with detectable AMH. The incidence of female gonadal hormone failure was 55.3%. In univariate analysis, older age at HCT was associated with greater likelihood of gonadal failure (median age, 17.6 versus 13.9; P < .0001), whereas conditioning intensity (RIC versus MAC), TBI, chronic graft-versus-host disease requiring systemic therapy, and CED were not significantly associated with gonadal function. In multivariable analysis, age remained statistically significant (odds ratio [OR]. 1.11; 95% confidence interval [CI], 1.03 to 1.22) for each year increase; P = .012), Forty-four percent of the males had gonadal failure. In univariate analysis, older age (median, 16.2 years versus 14.4 years; P = .0005) and TBI dose (P = .002) were both associated with gonadal failure, whereas conditioning intensity (RIC versus MAC; P = .06) and CED (P = .07) were not statistically significant. In multivariable analysis, age (OR, 1.16; 95% CI, 1.06-1.27 for each year increase; P = .0016) and TBI ≥600 cGy (OR, 6.23; 95% CI, 2.21 to 19.15; P = .0008) remained significantly associated with gonadal failure. Our data indicate that RIC does not significantly mitigate the risk for gonadal failure in females or males. Age at HCT and (specifically in males) TBI use seem to be independent predictors of post-transplantation gonadal function and fertility status. All patients should receive pre-HCT infertility counseling and be offered appropriate fertility preservation options and be screened post-HCT for gonadal failure.
Subject(s)
Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Female , Male , Adult , Adolescent , Child , Retrospective Studies , Transplantation Conditioning/adverse effects , Young Adult , Fertility/physiology , Survivors/statistics & numerical data , Anti-Mullerian Hormone/blood , Gonads/physiology , Risk FactorsABSTRACT
BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.
Subject(s)
Hematopoietic Stem Cell Transplantation , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Humans , Child , Child, Preschool , Adolescent , Influenza A Virus, H3N2 Subtype , Vaccines, Inactivated , Antibody Formation , Transplant Recipients , Antibodies, Viral , Hemagglutination Inhibition TestsABSTRACT
Post-transplantation revaccination uptake of childhood vaccines in adult hematopoietic stem cell transplantation (HSCT) survivors is suboptimal, increasing the risk of infectious morbidity and mortality within this population. We systematically reviewed the literature for factors related to revaccination uptake, as well as the barriers and facilitators that affect successful revaccination. We conducted a scoping review searching PubMed, CINAHL, Embase, and Web of Science in March 2023. Two independent reviewers performed study selection using the complete dual review process. Data were extracted using a standard form. Factors were characterized as demographic, clinical, or social determinants of health that affected revaccination uptake. Barriers and facilitators were categorized using the constructs from the World Health Organization Behavioural and Social Drivers Framework. Our searches yielded 914 sources, from which 15 publications were selected (5 original research and 10 quality improvement initiatives). More than one-half of the reports listed factors associated with poorer uptake, predominately clinical factors, followed by social determinants of health, then demographic factors. Nearly all the reports described barriers to successful revaccination uptake, with most of these falling into the "practical issues" construct. Most of the reports described facilitators, nearly all related to health care system improvements associated with improved revaccination uptake. Although this review provides a good starting point for understanding impediments to successful revaccination after HSCT, this review reveals that we lack sufficient evidence to drive targeted interventions to improve uptake. More research is needed, focusing on survivors' voices to inform our knowledge of barriers and facilitators to complete revaccination after HSCT, exploring behavioral and social drivers within this population, and examining the care delivery models that may complicate vaccine delivery in this population.
Subject(s)
Delivery of Health Care , Hematopoietic Stem Cell Transplantation , Adult , Humans , Immunization, SecondaryABSTRACT
BACKGROUND: Providers must balance effective empiric therapy against toxicity risks and collateral damage when selecting antibiotic therapy for patients receiving hematopoietic cell transplant (HCT). Antimicrobial stewardship interventions during HCT are often challenging due to concern for undertreating potential infections. METHODS: In an effort to decrease unnecessary carbapenem exposure for patients undergoing HCT at our pediatric center, we implemented individualized antibiotic plans (IAPs) to provide recommendations for preengraftment neutropenia prophylaxis, empiric treatment of febrile neutropenia, and empiric treatment for hemodynamic instability. We compared monthly antibiotic days of therapy (DOT) adjusted per 1000 patient-days for carbapenems, antipseudomonal cephalosporins, and all antibiotics during two 3-year periods immediately before and after the implementation of IAPs to measure the impact of IAP on prescribing behavior. Bloodstream infection (BSIs) and Clostridioides difficile (CD) positivity test rates were also compared between cohorts. Last, providers were surveyed to assess their experience of using IAPs in antibiotic decision making. RESULTS: Overall antibiotic use decreased after the implementation of IAPs (monthly reduction of 19.6 DOT/1000 patient-days; P = .004), with carbapenems showing a continuing decline after IAP implementation. BSI and CD positivity rates were unchanged. More than 90% of providers found IAPs to be either extremely or very valuable for their practice. CONCLUSIONS: Implementation of IAPs in this high-risk HCT population led to reduction in overall antibiotic use without increase in rate of BSI or CD test positivity. The program was well received by providers.