Allogeneic Hematopoietic Stem Cell Transplantation Recipients Research Articles

Primary Preventive Care of Hematopoietic Stem Cell Transplantation Survivors: Time to Educate and Empower Recipients and Providers

Increasing use of hematopoietic stem cell transplantation (HCT) and improvements in recipient outcomes have led to a steady increase in the number of allogeneic HCT survivors. In addition to complications specific to the transplantation process, HCT recipients are at increased risk of developing cardiovascular disease (CVD) and subsequent neoplasm (SN). Strict surveillance of risk factors for CVD and cancer in the general population is recommended as an essential component of long-term follow-up (LTFU) care of HCT survivors, but implementation of this has been suboptimal. Various models for improving the provision of survivorship care have been proposed, including a hybrid/combined care approach wherein the HCT provider manages transplantation-specific complications and the primary care physician (PCP) provides general medical care, including surveillance and aggressive management of CVD risk factors and screening for SN. This model also offers a practical approach to LTFU care for HCT survivors who live at a distance from the HCT center, which is a reality for many recipients of HCT at The Ottawa Hospital (TOH). As the success of such a hybrid approach to survivorship care depends on the engagement of HCT recipients with their PCP and compliance with recommended general population surveillance, the aim of the present study was to assess the rates of PCP attendance and adherence to recommended preventive medicine interventions in the years immediately before and after HCT. We hypothesized that rates would be suboptimal and planned to use these results as a baseline for an educational initiative aimed at increasing awareness of HCT recipients and their PCPs about embracing preventive survivorship care. This was a single-center cohort study of allogeneic HCT recipients who underwent transplantation at TOH with linkage to population-based health administrative data. Published clinical practice guidelines were used to define recommended screening for CVD risk factors and cancer. The rates of annual PCP visits and utilization of recommended preventive care interventions in the 5 years before and after HCT were calculated for all eligible patients. Between 2014 and 2020, 409 patients with provincial health care coverage underwent allogeneic HCT at TOH. The median patient age was 51 years (range, 15 to 73 years), with a male predominance (60.9%). Approximately one-quarter of recipients did not attend a PCP visit in the 5 years before and after transplantation, and this proportion increased to one- third in the fifth year post-HCT. Among those recipients who were eligible, only 20% to 25% underwent recommended screening for dyslipidemia and diabetes. Cancer screening rates were also low, at 16% to 18% for cervical cancer, 18% to 22% for colon cancer, and 30% to 31% for breast cancer. These results highlight the need to increase awareness of HCT recipients and their PCPs about the risk of developing CVD and SN post-transplantation and to emphasize the potential to mitigate this risk by adhering to recommendations for surveillance to enable prompt intervention. Patient education should incorporate this information and empower HCT survivors to actively engage in their follow-up care and optimize their long-term outcomes.

MRNA-1273 SARS-CoV-2 vaccine safety and COVID-19 risk perception in recently transplanted allogeneic hematopoietic stem cell transplant recipients.

PurposeThis study aims to describe the incidence and severity of adverse events (AEs) following the mRNA-1273 SARS-CoV-2 vaccine and explore the risk perception of COVID-19 in allogeneic hematopoietic stem cell transplant (HCT) recipients.MethodsWe performed a single-center prospective study including recently transplanted (< 2 years post-infusion) allogeneic HCT recipients. AEs were assessed through phone calls and graded from 0 to 4, while COVID-19 risk perception was measured using the Brief Illness Perception Questionnaire (BIP-Q5).ResultsFifty-four HCT recipients were evaluated. Incidence and grades of AE (94.4% and 85.2% after the first and second dose, respectively) were similar to those described in the general population. The most common AE was pain at the site of injection. Three patients (5.6%) developed a grade ≥ 3 AE. Vaccine-related cytopenias and graft-versus-host disease flares were not observed. Female sex (OR 3.94, 95% CI 1.14–13.58, p = 0.03) and time since HCT (per month since HCT: OR 1.09, 95% CI 1.01–1.18, p = 0.04) were associated with the occurrence of any AE. The patients’ risk perception level of COVID-19 decreased over time (p < 0.05).ConclusionOur study confirms that the mRNA-1273 SARS-CoV-2 vaccine is safe in recent HCT recipients and suggests that the perceived risk of COVID-19 decreases over time.

424.1: Epidemiology of Cytomegalovirus Infection and Disease in Hematopoietic Stem Cell Transplant Recipients in Selected Countries Outside of North America and Europe: A Systematic Review

Background: Cytomegalovirus (CMV) is a highly prevalent herpes virus with a seroprevalence higher in South America, Africa, and Asia than in Europe and North America. In hematopoietic stem cell transplant recipients (HSCT), CMV infection is a common opportunistic infection and a major cause of morbidity and mortality. To better understand the epidemiology of CMV infection and disease post-HSCT in selected countries outside of Europe and North America, a systematic review was conducted. Methods: Observational studies that included HSCT recipients (any age) from 15 selected countries in Asia-Pacific, Latin America, Russia and the Middle East were considered (search period: 01 Jan. 2011 – 21 Jul. 2021). Outcomes of interest were incidence, recurrence rates and risk factors of CMV infection and CMV disease, and CMV-related mortality at any time point. Indexed publications (Ovid® MEDLINE and Embase, Cochrane Database of Systematic Reviews and World Health Organization database Global Index Medicus) were searched, supplemented by pragmatic searches of the grey literature and snowballing of references lists. The protocol was registered in PROSPERO (CRD42020205559). Results: A total of 63 studies (range: 33 to 10,206 patients), most conducted in adults (≥ 18 years; n=49 studies, 77.8%) and allogeneic HSCT recipients (n=53, 84.1%), were included in the review. In 43 of 54 studies reporting on incidence of CMV infection, within 1 year post-HSCT, estimates were uniformly distributed between 24.8% and 61.2% (Figure 1). Lower estimates were reported in autologous HSCT recipients (5.3%), and younger patients at the time of transplantation (9.3% in adults with a median age of 25 years and 18.6% in patients aged ≤20 years). Higher estimates (range: 69.4% to 88.2%) were found in 8 studies from China and South Korea, most with a follow-up period > 1 year (median: 27 to 54 months in 5 studies) (Figure 2). Incidence of CMV disease following HSCT was below 20%, with estimates uniformly distributed between 0% and 15.7% in allogeneic HSCT. According to 11 studies, reported rates of CMV recurrence ranged between 19.8% and 37.9%. Commonly reported risk factors for CMV infection or disease in HSCT recipients were high-risk CMV serostatus (R+) (hazard ratio [HR]: 2.6 and 3.7, odds ratio [OR]: 2.2 and 5.4), older age of recipients (HR for each additional year: 1.03-1.04), presence of acute or chronic graft versus host disease (HR: 1.1-2.5), haploidentical HSCT (HR: 2.7-6.4), and use of immunosuppressive agents (OR: 5.0-9.3). CMV-related mortality was reported in up to 10% of patients following HSCT (n=30 studies; period of assessment not reported). Conclusion: Relatively high rates of CMV infection, CMV disease and CMV recurrence were reported post-HSCT, with CMV-related mortality observed in up to 1 in every 10 patients. High rates of CMV infection and disease post-HSCT may impact graft outcomes and increase disease burden in patients post-transplantation.This review was funded by Takeda International AG – Singapore Branch. CMM has received honoraria from Takeda and MSD (advisory board, speaker, educational events, meeting). S-YC has served as a consultant for Takeda Pharmaceutical, and has received research support and payment for lectures from Merck Sharp & Dohme, Pfizer and Gilead. MS has received grants from F2G, Gilead, Merck and personal fees from Gilead, Pfizer, Takeda and Roche for work outside of this research; IS is an employee of Takeda Pharmaceuticals India Pvt Ltd. AS and DD are employees of Takeda International AG – Singapore Branch and hold stock options. WD has no conflicts of interest to disclose. Literature retrieval, analysis and medical writing support were provided by Aurore Bergamasco, Camille Goyer, and Yola Moride of YolaRX Consultants and funded by Takeda International AG – Singapore Branch.

424.9: Real-World Treatment Patterns and Outcomes For Cytomegalovirus Infection and Disease in Hematopoietic Stem Cell Transplant Recipients in Selected Countries Outside of North America and Europe: A Systematic Review

Background: There is a paucity of real-world data on treatments used for cytomegalovirus (CMV) in hematopoietic stem cell transplant (HSCT) recipients, which differ across countries, outside of developed markets. To address this knowledge gap, a systematic review was conducted to evaluate current treatment patterns for CMV infection and disease following HSCT in selected countries outside of North America and Europe and describe related outcomes. Methods: Information sources (search period: 01 Jan. 2011 – 21 Jul. 2021) included indexed literature (Ovid® MEDLINE and Embase, Cochrane Database of Systematic Reviews and World Health Organization database Global Index Medicus), conference abstracts, pragmatic searches of the grey literature and snowballing of references lists of retained studies. Observational studies of interest included HSCT recipients (any age) who developed CMV infection or disease in 15 selected countries in Asia-Pacific, Latin America, Russia, and the Middle East. Outcomes of interest were treatment patterns for CMV infection and CMV disease, proportion of patients (pts) with resistant and refractory CMV including definitions, treatment-related outcomes and adverse events (AEs). The protocol was registered in PROSPERO (CRD42020205559). Results: Out of 25 retained studies (33 to 475 pts), most included allogeneic HSCT recipients (n=21, 84.0%) and adult pts (n=20, 80.0%). In HSCT recipients, pre-emptive therapy with intravenous ganciclovir (IV GCV) and/or valganciclovir (VGCV) is the conventional first-line (1L) approach for CMV infection prevention, with a median treatment duration of 14-24 days (5 studies). GCV IV was also the conventional treatment for CMV disease (5 studies), with treatment lasting 12-30 days (3 studies). Neutropenia was observed in 30.0% and 39.8% pts treated with GCV and, in 3 studies, neutropenia, myelosuppression, and nephrotoxicity led to GCV discontinuation, respectively, in 13.6%, 10.0%, and 2.3% of pts. In 3 studies, up to 10.0% of pts had second-line (2L) treatment with foscarnet, due to GCV-related myelosuppression. The reported proportion of pts with resistant CMV (definition not specified) ranged between 0% and 7.7% (5 studies; Figure 1). These pts received foscarnet or cidofovir as 2L therapy for a mean duration of 14 days (no data on AEs reported). In 3 studies, estimates of refractory CMV were 2.9%, 13.0%, and 49.4% (latter estimate reported in 39 pts, of whom 56.0% had recurrent CMV). Conclusion: In selected countries outside of North America and Europe, conventional therapeutic options for pre-emptive and treatment of CMV infection and CMV disease following HSCT were IV GCV and VGCV. However, premature treatment discontinuation occurred in up to 1 in 8 pts, highlighting an unmet need with current standard of care. Real-world outcomes in pts with refractory CMV (with or without resistance) were scarce and warrants further investigation in this patient population, including therapeutic management.This review was funded by Takeda International AG – Singapore Branch. S-YC has served as a consultant for Takeda Pharmaceutical, and has received research support and payment for lectures from Merck Sharp & Dohme, Pfizer and Gilead. WD has no conflicts of interest to disclose. CMM has received honoraria from Takeda and MSD (advisory board, speaker, educational events, meetings). IS is an employee of Takeda Pharmaceuticals India Pvt Ltd. AS and DD are employees of Takeda International AG – Singapore Branch and hold stock options. MS has received grants from F2G, Gilead, Merck and personal fees from Gilead, Pfizer, Takeda and Roche for work outside of this research. Literature retrieval, analysis and medical writing support were provided by Aurore Bergamasco, Camille Goyer, and Yola Moride of Yolarx Consultants and funded by Takeda International AG – Singapore Branch.

Vaccine Adherence and Postvaccination Serological Status of Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single-center Experience.

Despite developing consensus guidelines addressing immunization after hematopoietic stem cell transplantation (HSCT), studies showed deviations from recommended immunization practices commonly occur. Difference between the ideal scenario presented in guidelines and real-life scenarios is one of the most recognized barriers to implementing recommended practices. Therefore, this study aimed to evaluate pediatric allogeneic HSCT recipients' adherence to revaccination schedule and evaluate the serological status after immunization. Transplant and vaccination records of children who were followed up at least 2 years after HSCT, postvaccination antibody results of vaccine-preventable diseases were evaluated retrospectively. Total of 173 patients have enrolled in this study. Median revaccination onset time was post-transplant 15 months. Adherence to revaccination program was 30% for inactive and 11.4% for live vaccines. Oral polio vaccine was given to 22 patients, and Bacille-Calmette-Guerin vaccine was applied to 3. Seropositivity after revaccination was >90% for Hepatitis B, Hepatitis A, pertussis, and measles, and it was 88.5% for rubella, 80% for mumps and varicella. Measles seropositivity was low in children with hemoglobinopathy. In subgroup assessments of pertussis, patients vaccinated with low antigen-containing pertussis vaccine (Tdap) had higher seropositivity of adenylate cyclase toxin. Our findings revealed the importance of careful monitoring of current practices in pediatric HSCT recipients.

Serologic response and safety of COVID-19 vaccination in HSCT or CAR T-cell recipients: a systematic review and meta-analysis

BackgroundPatients receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR T-cell) therapy are immunocompromised and at high risk of viral infection, including SAR2-CoV-2 infection. However, the effectiveness and safety of COVID-19 vaccines in these recipients is not well characterized. The present meta-analysis evaluated the serologic response and safety of COVID-19 vaccines in these population.MethodsLiterature databases (MEDLINE, EMBASE, Web of Science, MedRvix and BioRvix) were searched for original studies with serologic response post COVID-19 vaccination in HSCT or CAR T-cell recipients published until July 14, 2022. The analysis included 27 observational studies with a total of 2899 patients receiving allogeneic HSCT (2506), autologous HSCT (286) or CAR T-cell therapy (107), and 683 healthy participants with serologic response data. Random effects models were used to pool the rate of serologic response to COVID-19 vaccination in HSCT or CAR T-cell recipients and odds ratio comparing with healthy controls.ResultsThe pooled seropositivity rates in HSCT and CAR T-cell recipients were 0.624 [0.506–0.729] for one dose, 0.745 [0.712–0.776] for two doses. The rates were significantly lower than those in healthy controls (nearly 100%). In subgroup analysis, CAR T-cell recipients exhibited an even lower seroconversion rate (one dose: 0.204 [0.094–0.386]; two doses: 0.277 [0.190–0.386]) than HSCT counterparts (one dose: 0.779 [0.666–0.862]; two doses: 0.793 [0.762–0.821]). The rates were comparable between autologous and allogeneic HSCT recipients. Other possible impact factors related to seropositivity were time interval between therapy and vaccination, use of immunosuppressive drugs and immune cell counts. Most vaccine-related adverse effects were mild and resolvable, comparable to general population.ConclusionsThis analysis revealed a diminished response to COVID-19 vaccines in HSCT or CAR T-cell recipients. Our findings may inform regular COVID-19 vaccination at appropriate intervals after HSCT or CAR T-cell therapy.

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation.

Letermovir has been approved as a novel cytomegalovirus (CMV) prophylactic agent after allogeneic hematopoietic stem cell transplantation (HSCT). However, there are still insufficient data to properly evaluate the real-world role of letermovir, and the risk factors for CMV reactivation under letermovir prophylaxis have not been clarified. We performed a single-institution retrospective analysis of patients under prophylaxis with or without letermovir who underwent allogeneic HSCT between March 2012 and December 2019. In August 2018, letermovir was added to the clinical practice at our institution for the prophylaxis of CMV reactivation in allogeneic HSCT recipients. Patients who underwent HSCT without prophylactic letermovir from March 2012 until September 2018 served as a historical control. The cumulative incidence of clinically significant CMV infection (CS-CMVi) was significantly lower in the letermovir group than in the historical control group not receiving letermovir (30.2%vs. 71.6%, p < .05, at 100 days). In addition, the cumulative incidence of non-relapse mortality (NRM) at day 500 was significantly lower in the letermovir group (4.7%vs. 19.8%, p < .05). We then performed a risk factor analysis for developing CS-CMVi in the letermovir group. The only significant factor identified by this multivariable analysis was transplantation from a CMV seronegative donor to a seropositive recipient (Hazard ratio = 2.76, 95% confidence interval 1.14-6.68, p < .05). Our study showed that letermovir prophylaxis significantly reduced the incidence of CS-CMVi and NRM in a real-world setting and that the CMV serostatus of the donor remained as a risk factor for CS-CMVi even under letermovir prophylaxis.

Breakthrough Covid-19 infections in vaccinated recipients of allogeneic stem cell transplantation.

Breakthrough Covid-19 infections in vaccinated recipients of allogeneic stem cell transplantation.

Clinical Characteristics and Outcomes of COVID-19 in Pediatric and Early Adolescent and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Cohort Study

Adult hematopoietic stem cell transplantation (HSCT) recipients are at a high risk of adverse outcomes after COVID-19. Although children have had better outcomes after COVID-19 compared to adults, data on risk factors and outcomes of COVID-19 among pediatric HSCT recipients are lacking. We describe outcomes of HSCT recipients who were ≤21 years of age at COVID-19 diagnosis and were reported to the Center for International Blood and Marrow Transplant Research between March 27, 2020, and May 7, 2021. The primary outcome was overall survival after COVID-19 diagnosis. We determined risk factors of COVID-19 as a secondary outcome in a subset of allogeneic HSCT recipients. A total of 167 pediatric HSCT recipients (135 allogeneic; 32 autologous HSCT recipients) were included. Median time from HSCT to COVID-19 was 15 months (interquartile range [IQR] 7-45) for allogeneic HSCT recipients and 16 months (IQR 6-59) for autologous HSCT recipients. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (1-179) for allogeneic and autologous HSCT recipients, respectively. Although COVID-19 was mild in 87% (n = 146/167), 10% (n = 16/167) of patients required supplemental oxygen or mechanical ventilation. The 45-day overall survival was 95% (95% confidence interval [CI], 90-99) and 90% (74-99) for allogeneic and autologous HSCT recipients, respectively. Cox regression analysis showed that patients with a hematopoietic cell transplant comorbidity index (HCT-CI) score of 1-2 were more likely to be diagnosed with COVID-19 (hazard ratio 1.95; 95% CI, 1.03-3.69, P = .042) compared to those with an HCT-CI of 0. Pediatric and early adolescent and young adult HSCT recipients with pre-HSCT comorbidities were more likely to be diagnosed with COVID-19. Overall mortality, albeit higher than the reported general population estimates, was lower when compared with previously published data focusing on adult HSCT recipients.

Impact on outcomes of mixed chimerism of bone marrow CD34+ sorted cells after matched or haploidentical allogeneic stem cell transplantation for myeloid malignancies.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT), proposed to patients with high-risk myeloid malignancies, may ultimately fail because of disease relapse. Bone marrow (BM) CD34+ cells in Allo-HSCT recipients can be either re-emerging recipient malignant cells or donor cells attesting of hematopoietic reconstitution. In this context, investigating donor/recipient chimerism in the population of BM CD34+ sorted cells (BM-CD34+SC) was performed in 261 Allo-HSCT recipients (matched n = 145, haploidentical n = 65, matched unrelated n = 51) with myeloid malignancies. BM-CD34+SC chimerism was compared to that of whole peripheral blood (PB) cells as well as other Allo-HSCT-related parameters, and impact on relapse and survival was assessed. Thresholds of 98% donor cells for PB and 90% for BM-CD34+SC were found to allow relapse prediction. This was completed by the application of machine learning tools to explore the predictive value of these parameters in multidimensional models with repeated iterations. BM-CD34+SC mixed chimerism stood out with all these methods as the most robust predictor of relapse with a significant impact on disease-free and overall survivals even after haploidentical Allo-HSCT and/or PTCY administration. This marker therefore appears to be of great interest for the decision of preemptive treatment to avoid post-transplant relapse.

Cellular Immune Response after Vaccination with an Adjuvanted, Recombinant Zoster Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplant (HSCT) recipients have a high risk of developing primary varicella-zoster virus (VZV) infection and reactivation. VZV vaccination may prevent infection and reactivation. In the current study, recipients of allogeneic HSCT (34 females, 45 males) were vaccinated with adjuvanted, recombinant zoster vaccine Shingrix™, which contains the VZV glycoprotein E. Cellular immunity against various VZV antigens was analyzed by interferon-gamma ELISpot. Peripheral blood mononuclear cells (PBMC) of recipients with versus without prior shingles (n = 36 and n = 43, respectively) showed approximately twofold higher VZV-specific responses prior to and post vaccination. After the first and second vaccination, ELISpot responses towards the glycoprotein E were significantly higher in males versus females (median of spots increment 18 versus 1 and 17 versus 4, respectively, p ≤ 0.02 each). Multivariate analysis showed that shingles and sex both impacts significantly on VZV immunity. Whereas vaccination-induced changes could hardly be detected after stimulation with a whole VZV antigen, there was a significant increase in responses towards glycoprotein E after vaccination (p < 0.005). These data indicate that vaccination with Shingrix™ augmented cellular, VZV-specific immunity in HSCT recipients. Shingles and male sex could both be identified as factors leading to increased immunity.

Peer support in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT): a qualitative study.

Peer support, a distinctive form of social support in which patients share emotional, social, and practical help based on their own lived experience of illness and treatment, positively impacts patient-reported outcomes in cancer populations. However, data on peer support experiences among hematopoietic stem cell transplant (HSCT) recipients are limited. We conducted semi-structured qualitative interviews among 12 allogeneic HSCT recipients who were ≤6 months post transplant without any complications and 13 allogeneic HSCT recipients >6 months post transplant and living with chronic graft-versus-host disease. Interviews explored patients’ experiences with peer support and their preferences for a peer support intervention tailored to the needs of HSCT recipients. While the majority (70%) of participants reported no formal experience with peer support, most (83%) articulated themes of potential benefits of peer support (e.g., managing expectations and uncertainty that accompany HSCT). Most participants (60%) reported a preference for a peer support intervention prior to the HSCT hospitalization. Despite the limited data on peer support interventions among HSCT recipients and lack of formal peer support experience in most of our cohort, our study shows that HSCT recipients clearly acknowledge the potential benefits of a peer support intervention, and they prefer that it start prior to transplantation.

Pediatric Vulvovaginal Graft-Versus-Host Disease: A Retrospective Cohort Study and Literature Review

Study ObjectiveTo assess genital symptomatology, characterize the findings of genital examination, and describe the incidence and treatment of vulvovaginal graft-versus-host disease (vvGvHD) in girls and adolescents after allogeneic hematopoietic stem cell transplantation (HSCT). DesignRetrospective cohort. SettingMetropolitan-area children's hospital. ParticipantsFemale allogeneic HSCT recipients ages 0 to 22 years. Main Outcome MeasuresGenital symptoms, genital examination, diagnosis, and treatment of vvGvHD. ResultsA total of 57 participants were included in the analysis. The median age at the time of HSCT was 10 years (range 4 months−23 years). Most (n = 40, 71%) underwent transplant for a nonmalignant condition, most commonly sickle cell anemia (n = 19, 33%). The median time of onset of GvHD post HSCT was 62 days (IQR = 42 to 151 days). The most common initial site of GvHD was skin (n = 21, 64%), followed by GI tract (n = 10, 30%). Three patients (5%) were diagnosed with vvGvHD. The time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. One patient (33%) was asymptomatic at the time of diagnosis. There was no difference in diagnosis of vvGvHD when race (P = 0.15), age at allogeneic HSCT (P = 0.64), nonmalignant vs malignant indication (P = 0.21), source of stem cells (P = 0.25), partial vs full human leukocyte antigens (HLA) donor match (P = 0.34), and GvHD prophylaxis regimen (P = 0.18) were compared. None had isolated vvGvHD. Vulvovaginal GvHD was preceded by skin GvHD in 1 patient, was preceded by lung GvHD in 1 patient, and occurred concurrently with skin GvHD in the third patient. ConclusionsPediatric vvGvHD can occur within the first 100 days after transplant and can be asymptomatic. Routine gynecologic evaluation post allogeneic HSCT in children and adolescents should include a thorough review of vulvovaginal symptoms and a gynecologic exam for the detection and treatment of vvGvHD.

Chronic kidney disease, survival and graft-versus-host-disease-free/relapse-free survival in recipients of allogeneic hematopoietic stem cell transplant.

ABSTRACTBackgroundAdvances in allogeneic hematopoietic stem cell transplant (HSCT) have increased patient survival, although substantial treatment-related toxicity remains, including chronic kidney disease (CKD). We assessed the association between CKD and survival and transplant-specific outcomes in HSCT recipients.MethodsWe conducted a retrospective study of all 408 adult patients with allogenic HSCT at Princess Margaret Cancer Centre (Toronto, Canada, 2015–18). We used logistic regression to identify risk factors for CKD at 1 year post-transplant. Associations between CKD at 1 year and overall survival, relapse-free survival, graft-versus-host-disease (GVHD)-free/relapse-free survival, relapse and transplant-related mortality were examined using extended time-varying Cox models. In a sensitivity analysis, we restricted the cohort to survivors at 1 year, using standard Cox proportional hazard models to examine associations between CKD and overall survival, relapse-free survival and GVHD-free/relapse-free survival, and Fine and Gray's competing risk models to determine associations between CKD and relapse/transplant-related mortality.ResultsThe prevalence of CKD at 1 year was 19% (46 patients) with median follow-up of 23 months. Multivariable regression identified age at transplant [adjusted OR (aOR) 1.09, 95% confidence interval (95% CI) = 1.05–1.14; P < 0.0001), female gender (aOR 2.83, 95% CI = 1.34–5.97; P = 0.006) and acute kidney injury during the first 100 days (aOR 3.86, 95% CI = 1.70–8.73; P = 0.001) as risk factors for CKD at 1 year. Patients with CKD at 1 year had significantly poorer overall survival than those without CKD, when adjusted for relevant covariates [adjusted HR (aHR) 1.93, 95% CI = 1.02–3.66; P = 0.04 in the time-varying Cox model, and aHR 2.06, 95% CI = 1.04–4.07; P = 0.04 using the standard Cox model]. CKD at 1 year was also associated with worse GVHD-free/relapse-free survival (aHR 1.65, 95% CI = 1.04–2.61; P = 0.03).ConclusionsCKD adversely affects the long-term prognosis for allogeneic HSCT recipients, with increased mortality risk and worse GVHD-free/relapse-free survival.

SARS-CoV-2 T-Cell Responses in Allogeneic Hematopoietic Stem Cell Recipients following Two Doses of BNT162b2 mRNA Vaccine.

Background: At variance to humoral responses, cellular immunity after anti-SARS-CoV-2 vaccines has been poorly explored in recipients of allogeneic hematopoietic stem-cell transplantation (Allo-HSCT), especially within the first post-transplant years where immunosuppression is more profound and harmful. Methods: SARS-CoV-2 Spike protein-specific T-cell responses were explored after two doses of BNT162b2 mRNA vaccine in 45 Allo-HSCT recipients with a median time from transplant of less than 2 years by using INF-γ ELISPOT assay and flow-cytometry enumeration of CD4+ and CD8+ T lymphocytes with intracellular cytokine production of IFN-γ and TNF-α. Results: A strong TNF-α+ response from SARS-CoV-2-specific CD4+ T-cells was detected in a majority of humoral responders (89%) as well as in a consistent population of non-humoral responders (40%). Conclusions: T-cells are likely to participate in protection against COVID-19 viral infection, even in the absence of detectable antibody response, especially in the first years post-transplant in Allo-HSCT recipients.

Cytokine Release Syndrome during Antithymocyte Globulin/Anti-T Lymphocyte Globulin Serotherapy for Graft-versus-Host Disease Prophylaxis before Allogeneic Hematopoietic Stem Cell Transplantation: Incidence and Early Clinical Impact According to American Society of Transplantation and Cellular Therapy Grading Criteria

Antithymocyte globulin (ATG)/anti-T lymphocyte globulin (ATLG) aids graft-versus-host disease (GVHD) prophylaxis in HLA-matched related and unrelated donor hematopoietic stem cell transplantation (HSCT). Its use is frequently accompanied by systemic infusion reactions attributable to cytokine release syndrome (CRS). However, detailed data on ATG/ATLG-induced CRS and its correlation with clinical outcome parameters are lacking. This study aimed to analyze the incidence, characteristics, risk factors, and early clinical impact of CRS during ATG/ATLG administration before allogeneic HSCT according to the American Society of Transplantation and Cellular Therapy (ASTCT) CRS grading criteria. This retrospective single-center analysis included consecutive recipients of allogeneic HSCT treated with ATG/ATLG as GVHD prophylaxis at the Medical University of Vienna between January 1, 2014, and August 15, 2021. Multivariate regression models were used to explore risk factors for CRS and its association with clinical outcomes (acute GVHD grade II-IV, clinically significant cytomegalovirus infection, nonrelapse mortality, and overall survival) at 6 months after HSCT. A total of 284 patients (median age, 54 years; interquartile range [IQR], 45 to 61 years; 120 females, 164 males) were included in the study. ATLG was used in 222 patients (78%); ATG, in 62 (22%). One hundred sixty-six patients (58%) developed CRS grade ≥1 during ATG/ATLG administration. CRS was mostly mild, with 92% of the cases CRS grade 1-2. Thirteen patients (5%) developed CRS grade 3, and 1 patient had CRS grade 4. No CRS-related death (grade 5) occurred. Patients with CRS showed a pronounced systemic inflammatory response as measured by inflammatory markers C-reactive protein, IL-6, and procalcitonin. In multivariate analysis, lymphoma as the underlying disease, high ATLG dose of 60 mg/kg, and body weight were significantly associated with CRS. Patients with CRS grade ≥1 had a higher 6-month incidence of acute GVHD II-IV compared with patients without CRS (24% versus 14%; P=.04). This effect remained statistically significant only for CRS grade 3-4 (subdistribution hazard ratio, 3.70; 95% confidence interval, 1.58 to 8.68; P < .01) after adjusting for relevant confounders. Other clinical outcome parameters were not affected by the occurrence of CRS. In our cohort, CRS defined by ASTCT grading was a frequent but mostly mild complication following ATG/ATLG administration for GVHD prophylaxis. Our data suggest a possible interaction of (higher-grade) CRS with an increased risk for developing acute GVHD. Further studies to corroborate this finding are warranted, as it could inform the investigation of additional prophylactic interventions, such as IL-6 blockade, in this setting.

Scheduled administration of virus-specific T cells for viral prophylaxis after pediatric allogeneic stem cell transplant

AbstractInfections with double-stranded DNA viruses are a significant cause of morbidity and mortality in pediatric patients following allogeneic hematopoietic stem cell transplantation (HSCT). Virus-specific T-cell therapies (VSTs) have been shown to be an effective treatment for infections with adenovirus, BK virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). To date, prophylactic regimens to prevent or mitigate these infections using conventional antiviral medications provide suboptimal response rates. Here we report on a clinical trial (NCT03883906) performed to assess the feasibility of rapid manufacturing and early infusion of quadrivalent VSTs generated from stem cell donors (“donor-derived VSTs”) into allogeneic HSCT recipients with minimal or absent viremia. Patients were eligible to receive scheduled VSTs as early as 21 days after stem cell infusion. Twenty-three patients received scheduled VSTs. Twenty of 23 patients had no viremia at the time of infusion, while 3 patients had very low-level BK viremia. Two developed clinically significant graft-versus-host disease (GVHD), although this incidence was not outside of expected incidence early after HSCT, and both were successfully treated with systemic corticosteroids (n = 2). Five patients were deemed treatment failures. Three developed subsequent significant viremia/viral disease (n = 3). Eighteen patients did not fail treatment, 7 of whom did not develop any viremia, while 11 developed low-level, self-limited viremia that resolved without further intervention. No infusion reactions occurred. In conclusion, scheduled VSTs appear to be safe and potentially effective at limiting serious complications from viral infections after allogeneic transplantation. A randomized study comparing this scheduled approach to the use of VSTs to treat active viremia is ongoing.

Anti-Xa based dosing of enoxaparin in hematopoietic stem cell transplant and adoptive cell therapy patients: A single center experience

Patients undergoing hematopoietic stem cell transplantation (HSCT) and adoptive cell therapies (ACT) are at an increased risk of venous thromboembolism (VTE) [1,2]. A concurrently elevated risk of bleeding in the setting of thrombocytopenia, graft versus host disease (in recipients of allogeneic HSCT) and coagulopathy complicates therapeutic anticoagulation (TAC) in this patient population [3,4]. TAC, when administered to HSCT and ACT patients in the peri-transplant setting at our center, is achieved with the low-molecular weight heparin (LMWH) enoxaparin.

Monitoring of resistanceassociated mutations in UL97 gene of cytomegalovirus in children after allogeneic hematopoietic stem cell transplantation

Objective. To perform genotyping of cytomegalovirus (CMV) phosphotransferase UL97 and investigate mutations associated with ganciclovir/valganciclovir (GCV/VGCV) resistance in children after allogeneic hematopoietic stem cell transplantation (HSCT) with confirmed CMV infection. Materials and Methods. This single-center prospective study was conducted from January 2020 to December 2021 and enrolled allogeneic HSCT recipients under 18 years of age with confirmed CMV infection. In case of possible GCV resistance, molecular genotyping with Sanger sequencing was performed. The search for mutations in the UL97 gene was carried out in the range of 425–670 codons. Results. Out of 168 patients with confirmed CMV infection, 72 patients met the criteria for possible resistance to GCV/VGCV. As a result of nucleotide sequencing of the CMV UL97 gene in 19 patients (11.3% of a total number of patients and 26.4% of patients meeting the resistance criteria) 11 genotypes of the following mutations were identified: H520Q, C592G, A594V, L595S, D605E, C603W, C607Y, C607F, M615V, M460V and E655K. The following mutations associated with resistance to HCV/VHCV: H520Q, C592G, A594V, L595S, C603W, C607Y, C607F, M460V were found in 12 patients (7% of a total number of patients and 9.7% of patients meeting the resistance criteria). Conclusions. Due to a high frequency of detection of the mutant form of phosphotransferase UL97 in allogeneic HSCT recipients with confirmed CMV infection, it is important to implement monitoring of resistant-associated mutations in order to administer appropriate antiviral therapy.

Bacteremia in Hematopoietic Stem Cell Recipients Receiving Fluoroquinolone Prophylaxis: Incidence, Resistance, and Risk Factors.

BackgroundBacteremia is a common complication in hematopoietic stem cell transplant (HSCT) recipients. Prophylactic fluoroquinolone is recommended and used in these individuals. Breakthrough infections can occur with fluoroquinolone-resistant strains. We aimed to identify the incidence, resistance, and risk factors for bacteremia in HSCT recipients receiving fluoroquinolone prophylaxis.Materials and MethodsThis retrospective study was performed on patients who received fluoroquinolone prophylaxis and underwent autologous and allogeneic HSCT between 2015 and 2019. The incidence of bacteremia, comorbidity, treatment, and invasive procedures was compared in these patients with and without bacteremia.ResultsThere were 553 patients included in the study, 68 (12.3%) had bacteremia. The incidence of bacteremia is 8.2% of autologous HSCT recipients and 18.4% of allogeneic HSCT recipients. The significant risk factors associated with bacteremia were steroid-using (odds ratio [OR]:13.83, 95% confidence interval [CI]: 2.88 - 66.40), higher Charlson Comorbidity Index (CCI)-mean (OR: 1.57, 95% CI: 1.15 - 2.16), diabetes mellitus (OR: 4.29, 95% CI: 1.11 - 16.48) in autologous HSCT, steroid-using (OR: 6.84, 95% CI: 1.44 - 32.33), longer duration of neutropenia (OR: 1.05, 95% CI: 1.01 - 1.09) using central venous catheter (OR: 7.81, 95% CI: 1.00 - 61.23) in allogeneic HSCT. Seventy-three pathogens were isolated from a total of 68 bacteremia episodes. The most commonly occurring agents were Escherichia coli, Klebsiella pneumoniae and Enterococcus spp. Resistance to fluoroquinolones was 87.2%, 70.0% and 60.0% among these strains, respectively.ConclusionHigh CCI, diabetes mellitus, use of steroids and long-term neutropenia and use of central venous catheters were significantly associated with the breakthrough bacteremia in HSCT recipients receiving fluoroquinolone prophylaxis. Fluoroquinolone prophylaxis may reduce the incidence of bacteremia but may select strains resistant to fluoroquinolone.