Hematopoietic Cell Transplantation Research Articles

Pre‐engraftment bacteremia after allogeneic hematopoietic cell transplantation without primary fluoroquinolone antibacterial prophylaxis

AbstractBackgroundBacteremia is a common complication in allogeneic hematopoietic cell transplant recipients (alloHCTr), especially during the pre‐engraftment period. International guidelines recommend antibacterial prophylaxis (ABP), despite potential selection for multidrug‐resistant organisms (MDRO). Limited contemporary data exist on the epidemiology of pre‐engraftment bacteremia in alloHCTr, who do not receive ABP.MethodsWe performed a retrospective observational single‐center cohort study including all consecutive adult alloHCTr (2015–2021), investigating the incidence, risk factors, and outcomes of bacteremia during the engraftment period. Primary fluoroquinolone (FQ) ABP is not routinely administered in our center.ResultsAmong 421 patients identified, 124 bacteremia episodes were observed in 121/421 (29%) alloHCTr. The median time to the 1st bacteremia episode was 9 days (IQR 6–11). Most (105/124, 85%) episodes were monomicrobial, while >1 pathogens were identified in 19/124 (15%) episodes. Overall, 152 pathogens were isolated, with a predominance of Gram‐positive (118/152, 78%), including coagulase‐negative staphylococci (n:47), streptococci (n:46), and enterococci (n:15), followed by Gram‐negative bacteria (GNB, 30/152, 20%), and anaerobes (4/152, 3%). There were 2/152 (1%) MDRO (extended‐spectrum beta‐lactamase producing) GNB. Multivariable analyses identified age >40‐year‐old (OR 2.4, P = 0.02), male gender (OR 1.8, P = 0.02), and a haploidentical/mismatched unrelated donor (OR 2.5, P < 0.001) as independent risk factors for bacteremia. All cause 30‐day mortality among alloHCTr with bacteremia was 0.8% (1/121): one patient died due to an HCT‐related complication.ConclusionDespite lack of primary FQ ABP, low rates of bacteremia were observed during the pre‐engraftment period, with low MDRO prevalence and mortality. Our findings may allow to revisit the need for primary universal FQ ABP in high‐risk neutropenic hematology patients. image

Abstract C044: Social vulnerability is an important predictor of cardiovascular disease risk after allogeneic hematopoietic cell transplantation

Abstract Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for malignant and non-malignant hematologic diseases. However, long-term HCT survivors have a >4-fold risk of developing cardiovascular disease (CVD) compared to the general population, and CVD is a leading cause of excess mortality after HCT. Comorbidities that emerge after HCT such as hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are important modifiers of CVD risk, but the impact of social determinants of health (SDOH) on the development of these risk factors and resultant CVD has not been well-characterized. Methods: This retrospective cohort study included 889 patients who underwent an allogenic HCT between 2013 and 2019 at City of Hope and survived ≥1y after HCT. Demographic, disease, treatment, comorbidity, and health outcomes data were abstracted from medical records. The social vulnerability index (SVI), obtained from the Center for Disease Control, represented overall social vulnerability and included 4 themes: socioeconomic status, household composition & disability, minority status & language, and housing & transportation. SVI scores were derived using patients’ addresses at time of HCT. SVI scores ranged from 0 (least vulnerable) to 100 (most vulnerable). Fine-Gray regression analysis evaluated the association between SVI and risk of HTN, DM, and DL, adjusted for age at HCT and treating death as competing risk. We also evaluated the association between having 0, 1, ≥2 cardiovascular risk factors on incidence of clinically significant CVD (heart failure, coronary artery disease, pericarditis, stroke, intracranial hemorrhage, arrhythmia, and/or valvular disease) after HCT. Results: Mean age at HCT was 44.2y (standard deviation 19.8y); 56.7% were male, 43.8% were non-Hispanic White, 35.4% were Hispanic, and 12.9% were Asian. The most common diagnosis was acute myeloid leukemia (39.6%); 48.6% received reduced intensity conditioning. Higher overall SVI was associated with increased risk of HTN (adjusted Hazard Ratio per 10 unit increase in SVI [aHR] 1.10, 95%CI 1.02-1.19) and DM (aHR 1.13, 95%CI 1.03-1.25). There was also an increased risk for DL for the highest SVI tertile for the housing & transportation theme (aHR 1.61, 95%CI 1.10-2.37). Accumulation of de novo risk factors after HCT was associated with an incremental 5y incidence of CVD (None: 6.1%, 95% CI 3.4%-9.9%; 1 risk factor: 15.7%, 95% CI 7.1%-27.3%; >2 risk factors: 31.6%, 95%CI 12.8%-52.4%; p<0.001). In the adjusted multivariable model, survivors with >2 risk factors had 7.0-fold (aHR 6.99, 95%CI 2.86-17.05) risk of CVD compared to those without (ref). Conclusion: Among allogeneic HCT recipients, higher SVI was associated with increased risk of HTN, DM, and DL after HCT, which in turn were associated with incrementally higher 5y incidence of CVD. These findings underscore the importance of SDOH on clinically important outcomes after allogeneic HCT, and may ultimately inform tailored approaches for risk-based screening and resource allocation in long-term survivors. Citation Format: Osariemen V Ogiamien, Sitong Chen, Lizel Atencio, Alysia Bosworth, Meagan Echevarria, Caitlyn Estrada, Mareen Kassabian, Lanie Lindenfeld, F. Lennie Wong, Saro H Armenian, Rusha Bhandari. Social vulnerability is an important predictor of cardiovascular disease risk after allogeneic hematopoietic cell transplantation [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C044.

Cellular and immunotherapies for myelodysplastic syndromes

In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS.

Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection

Abstract Background Among 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug. Methods Viral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment. Results Prior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug. Conclusion After 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy. Clinical Trials Registration NCT02927067 (AURORA)

The transplantation effect of pegylated granulocyte colony-stimulating factor mobilized hematopoietic stem cells may be superior to that of G-CSF mobilized hematopoietic stem cells in haploidentical allogeneic hematopoietic cell transplantation

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells have become the preferred source of hematopoietic stem cells. We compared the effectiveness of G-CSF and pegylated G-CSF (peg-G-CSF) for hematopoietic stem cell mobilization in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) donors, and evaluated the transplant outcomes. We conducted a matched retrospective cohort study. Donors mobilized with peg-G-CSF (n = 70) and G-CSF (n = 70). 140 consecutive patients diagnosed with acute leukemia who underwent haplo-HSCT were included in this study. The findings revealed that the peg-G-CSF cohort exhibited significantly elevated myeloid-derived suppressor cells (MDSCs) levels in their grafts when compared to the G-CSF cohort (P < 0.001). The 100-day cumulative incidence (CI) of grade III-IV acute graft-versus-host disease (GVHD) and 1-year CI of moderate-to-severe chronic GVHD were 4.3% vs 14.3 % (P = 0.047) and 11.2% vs 27.4 % (P = 0.023), in the peg-G-CSF group and G-CSF group. Patients reveiving mobilized stem cell with peg-G-CSF had a significantly greater likelihood of 1-year GVHD-free relapse-free survival (GRFS) compared to patients reveiving mobilized stem cell with G-CSF (74.9% vs 37.9 %, P < 0.001). The higher graft MDSCs proportion was associated with lower grade II-IV aGVHD, cGVHD (P < 0.05) and higher GRFS in the univariate analysis (P < 0.05). Multivariate analysis showed that MDSCs proportion higher than 11.36 % (HR, 0.305; 95 % CI, 0.154–0.606; P = 0.001) and peg-G-CSF for stem cell mobilization (HR, 0.466; 95 % CI, 0.251–0.865; P = 0.016) were independent prognostic factors of GRFS. The superior survival rates observed in recipients of peg-G-CSF-mobilized cells are likely due to reduced acute GVHD, potentially mediated by the increased MDSCs within the grafts.

Post-transplantation monitoring and quantitation of microparticles in allogeneic hematopoietic cell transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HCT) represents a curative treatment for various blood-related disorders, including hematological malignancies and genetic disorders. The success of this procedure hinges on the efficacy of the conditioning regimen and the graft's ability to engraft and function properly. Microparticles (MPs), small vesicles produced from stimulated, apoptotic, or activated cells, are involved in both physiological and pathological processes. However, the impact of MPs on allo-HCT remains poorly understood. ObjectivesThis study aimed to investigate the presence of MPs from different cell types in grafts and patient plasma after allo-HCT, as well as their association with various parameters. We measured MPs from CD34+, CD56+, CD3+, CD19+, and CD33+ cells in grafts and patient plasma from day 0 to day 60 after transplantation. Methods224 blood samples were collected from 19 consecutive allo –HCT recipients at 0, +4, +14,+30 and + 60 day as well as from their grafts. MPs isolated from the plasma and quantified by flow cytometry analysis. ResultsMP levels varied over time. Notably, CD34+ MP levels were linked to both early and late engraftment of neutrophils and platelets. Furthermore, grafts with high CD34+ and CD56+ MP levels in patient plasma on days 0 and + 4 were associated with late engraftment, whereas high CD33+ MP levels in both graft and patient plasma on day +4 were associated with early engraftment. Conditioning regimen affected CD19+ MP levels at day +14, and the number of CD34+, CD56+, and CD19+ MPs 30 days after transplantation was correlated with acute graft-versus-host disease. ConclusionThese findings suggest that MPs derived from hematopoietic cells may play a significant role in the clinical course of patients following allo-HCT.

Venetoclax-based salvage therapy as a bridge to transplant is feasible and effective in patients with relapsed/refractory AML

AbstractThe B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. Emerging data suggest that VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional treatment strategies for medically fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM) analysis, we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non–VEN-containing salvage therapy according to their treating physician’s choice (TPC), including intensive and nonintensive protocols. The overall response rate (complete remission [CR] + CR with incomplete hematologic recovery) among all VEN patients was significantly higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were successfully bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN cohort and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to NE) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (HR, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). In summary, our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML

PURPOSE Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate 131I-apamistamab with conventional care. METHODS SIERRA (ClinicalTrials.gov identifier: NCT02665065 ) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an 131I-apamistamab–led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the 131I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive 131I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population. RESULTS The ITT population included 153 patients (131I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received 131I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with 131I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P &lt; .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR &lt;1 favoring 131I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the 131I-apamistamab and conventional care groups, respectively. CONCLUSION The 131I-apamistamab–led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. 131I-apamistamab was well tolerated and could address an unmet need in this population.

Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age.

Utilization of hematopoietic cell transplantation (HCT) for hematologic cancers previously demonstrated race, ethnicity, and age-based disparities. To evaluate utilization over time by race, ethnicity, and age to determine if disparities persist in light of recent significant increases in HCT volume. This US population-based retrospective cohort study includes patients who received transplants from January 2009 to December 2018. Data collection and cleaning occurred from February 2019 to November 2021, and data analysis occurred from January 2022 to October 2023. Method 1 restricted the analysis to Surveillance, Epidemiology and End Results (SEER) reporting areas for cases and transplants. Method 2 applied SEER age-, race-, and ethnicity-specific incidence rates to corresponding US census population and included all transplants reported to the Center for International Blood and Marrow Transplant Research. Race and ethnicity groups were hierarchically defined as Hispanic (any race), non-Hispanic White, non-Hispanic Black, and non-Hispanic Other (Asian and American Indian). Receipt of HCT. Utilization rate of autologous or allogeneic HCT for patients with hematologic cancers by age, race, and ethnicity. From 2009 to 2018, 136 280 HCTs were analyzed for 6 hematologic cancers comprising 16.7% pediatric/adolescent/young adults (0-39 years), 83.3% adults (40-84 years), 58% male, 10.3% Hispanic, 11.4% non-Hispanic Black, 3.8% non-Hispanic Other, and 74.5% non-Hispanic White patients, with 49 385 allogeneic and 86 895 autologous HCTs performed. HCT utilization increased over time for all disease, age, race, and ethnic groups. From 2017 to 2018, adult (40-84 years) allogeneic transplant utilization for acute myeloid leukemia and myelodysplastic syndrome (MDS) was similar for Hispanic and non-Hispanic White or Other patients but was lower for non-Hispanic Black patients (acute myeloid leukemia: 19% vs 13%; MDS: 9%-10% vs 5%). Similarly, autologous transplant utilization for lymphoma was similar for all race and ethnicity groups; however, autologous transplant for multiple myeloma was highest for non-Hispanic White patients and lower for all other groups (31% vs 26%-27%). In patients aged 0 to 39 years, utilization of allogeneic transplant for acute lymphoblastic leukemia was highest in Hispanic patients, followed by non-Hispanic White, Black, and Other races (acute lymphoblastic leukemia: 19%, 18%, 17%, and 16%, respectively). In this cohort study of autologous and allogeneic transplant utilization for hematologic cancers, disparities persisted for non-Hispanic Black patients. Hispanic, non-Hispanic Other, and younger age groups had increased utilization over time that was on par with non-Hispanic White patients in the most recent cohort.

Alectinib maintenance therapy following cord blood transplantation for relapsed pediatric anaplastic large cell lymphoma with central nervous system involvement.

Pediatric ALK-positive anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphoma, and approximately 30% of patients relapse following treatment with conventional chemotherapy. Alectinib monotherapy has demonstrated excellent activity in relapsed and refractory ALCL, but its role as a maintenance therapy after hematopoietic cell transplantation is unclear. We experienced a relapse case of pediatric ALK-positive ALCL with central nervous system involvement treated with alectinib maintenance therapy following cord blood transplantation. The patient has maintained complete remission for more than 3 years after transplantation. There were no remarkable adverse effects that led to discontinuation of alectinib.

Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Among 111 patients of less than 20years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n=58) than in the pre-DF era (31% vs. 13%, p=.04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p=.04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p<.01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR]=10.4, p=.01) and juvenile myelomonocytic leukemia (OR=8.98, p=.04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

Histopathologic Analysis of Chronic Cutaneous Graft-Versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. Skin biopsy of cGVHD is recommended when clinical features are not diagnostic, yet the histopathologic features of skin cGVHD are not well described. The objective of this study is to describe the histopathologic features of skin cGVHD in epidermal, sclerotic, and combination cGVHD. Of 49 patients with skin cGVHD, 30 of 49 (61.2%) were male, and mean age was 55 years (SD 11.1). Clinically, 33 of 49 (67.3%) had epidermal cGVHD (E-cGVHD), 1 of 49 (2.1%) had sclerotic cGVHD (S-cGVHD), and 15 of 49 (30.6%) had combination disease. The 49 patients corresponded to 83 unique pathologic specimens with 67 of 83 (80.7%) taken from E-cGVHD, and 16 of 83 (19.3%) from S-cGVHD lesions. Nearly all biopsy specimens from E-cGVHD showed minimal features of active GVHD, including apoptosis in the epidermal basal layer (n = 63, 94.0%), vacuolar change (n = 62, 92.5%), and lymphocyte satellitosis (n = 57, 85.1%). The predominant histologic pattern of E-cGVHD was lichen planus/interface dermatitis (n = 31, 47.0%). S-cGVHD specimens also showed minimal features of active GVHD with apoptosis of the epidermal basal layer (n = 11, 68.8%) and vacuolar change (n = 8, 50.0%). In addition, S-cGVHD showed sclerosis of the papillary and reticular dermis and subcutaneous septae (n = 8, 50.0%; n = 11, 68.8%; n = 5, 31.2%, respectively). The predominant histologic pattern of S-cGVHD was lichen sclerosus/morphea-like pattern (n = 10, 62.5%). Although minimal pathologic features of active GVHD are common, the majority of cGVHD biopsies share features with the inflammatory skin diseases that they clinically resemble. Complete histologic reporting is recommended with implications for disease endotyping and personalized therapy.

Immunogenicity and Reactogenicity of High-dose or Standard-dose Influenza Vaccine in a Second Consecutive Influenza Season.

Pediatric hematopoietic cell transplant (HCT) recipients are at high-risk for morbidity from influenza virus infection. We demonstrated in a primary phase II randomized controlled trial that two post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart were more immunogenic than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen. A subcohort of study participants re-enrolled and had hemagglutinin inhibition (HAI) titers measured at baseline and four weeks after each vaccine dose in year two. We estimated geometric mean fold rise (GMFR) in HAI titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (aGMR, comparing HD-TIV to SD-QIV) for each antigen at each time point. We described systemic and injection-site reactions. A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Post-vaccine GMFR and aGMR estimates were higher for both groups following a single influenza vaccine dose in year two compared to two doses of the same formulation in year one. Both groups had similar frequencies of injection-site and systemic reactions. A single dose of HD-TIV or SD-QIV was more immunogenic in year two than two doses of the same formulation in year one. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a two-dose schedule in the prior year post-HCT.

Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.

Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood. To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor. This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months. National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers. Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available. Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (∼25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective. Cumulative incidence of transplantation by Search Prognosis arm. Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113). A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor. Trial Registration: NCT#03904134.

Galectin-1 is associated with hematopoietic cell engraftment in murine MHC-mismatched allotransplantation.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is associated with an increased risk of allograft rejection. Here, we employed a major histocompatibility complex (MHC)-mismatched allogeneic HCT (allo-HCT) murine model to better understand the role of Gal-1 in immune tolerance. Transplanted mice were classified into either rejected or engrafted based on donor chimerism levels. We noted significantly higher frequencies of CD4+ T cells, CD8+ T cells, natural killer cells, IFN-γ and TNF-α producing CD4+ T cells, and IFN-γ producing dendritic cells and macrophages in rejected mice. Conversely, we found significantly increased frequencies of regulatory T cells (Tregs), predominantly Helios+, IL-10-producing CD4+ T cells, type 1 regulatory (Tr1) cells, and the proportion of Tr1+Gal-1+ cells in engrafted mice. Further, Gal-1 specific blockade in Tregs reduced suppression of effector T cells in engrafted mice. Lastly, effector T cells from engrafted mice were more prone to undergo apoptosis. Collectively, we have shown that Gal-1 may favor HSC engraftment in an MHC-mismatched murine model. Our results demonstrate that Gal-1-expressing Tregs, especially at earlier time points post-transplant, are associated with inducing immune tolerance and stable mixed chimerism after HCT.

Biobehavioral mechanisms underlying symptoms in cancer patients with chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and high symptom burden. This study evaluated two biobehavioral mechanisms, inflammation and circadian rest-activity rhythms, that may underly commonly reported psychological and physical symptoms in cGVHD patients. Adults with cGVHD (N=57) wore a wrist actigraph for 7 days, provided a blood sample, and completed patient-reported outcome (PRO) measures. 24-hour rest-activity indices were derived from actigraphy. Cytokines and chemokines relevant to cGVHD were measured in peripheral blood plasma using multi-analyte immunoassays. Multiple regression evaluated the extent to which rest-activity indices and inflammatory biomarkers predicted PROs. Higher levels of circulating IL-8 and MIP-1α were associated with worse depression (β = 0.35, p = 0.01; β = 0.33, p = 0.02) and sexual function (β = -0.41, p = 0.01; β = -0.32, p = 0.03). MIP-1α was associated with more severe insomnia (β = 0.36, p = 0.01). Higher circulating MIF was associated with more severe anxiety (β = 0.28, p = 0.048) and fatigue (β = 0.35, p = 0.02). Il-6, TNFα, and MCP-1 showed few associations with PROs. There were few associations between actigraphy indices and PROs; however, participants with a later daily activity peak (acrophase) reported poorer sexual function (β = -0.31, p = 0.04). Models covarying for age, cGVHD severity, and time since HCT yielded a similar pattern of results. Results suggest that pro-inflammatory cytokines and chemokines associated with cGVHD may contribute to PROs, identifying a biobehavioral mechanism that may be a useful target for future interventions.

Immune cytopenia after paediatric haematopoietic cell transplantation

Immune cytopenia after paediatric haematopoietic cell transplantation

Clinical analysis of allogeneic hematopoietic cell transplantation in 9 patients with hematological malignancies complicated by Gilbert's syndrome

From January 1, 2013, to March 1, 2024, nine patients with hematological malignancies complicated by Gilbert's syndrome in Peking University People's Hospital underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients comprised seven male and two female cases, with a median age of 38 (13-60) years old. Among them, three cases were acute myeloid leukemia, three cases were acute lymphocytic leukemia, two cases were myelodysplastic syndrome, and one case was chronic myelomonocytic leukemia. None of the patients had viral hepatitis. Of the nine cases, seven cases received the Bu-Cy+ATG regimen, while the other two cases received the TBI-Cy+ATG regimen (Bu, busulfan; Cy, cyclophosphamide; ATG, antithymocyte immunoglobulin; and TBI, total body irradiation). All patients achieved neutrophil engraftment, and eight received platelet engraftment. The median total bilirubin level was 45.4 (22.5-71.2) μmol/L before transplantation and 22.0 (18.0-37.2) μmol/L on -1d of preconditioning. The total bilirubin level on +20d after the transplantation of eight patients decreased compared with the baseline level before transplantation. Moreover, one patient had a transient increase in the total bilirubin level on +5d after transplantation, which was considered to be attributed to the toxicity of Bu. No patients were complicated by hepatic veno-occlusive disease. The median follow-up time was 739 (42-2 491) days. During the follow-up period, one patient died of recurrence, and the remaining eight patients had disease-free survival events.

Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications.

Non-coding mismatches in HLA Class I genes in the presence of DPB1 mismatches predict worse outcomes in hematopoietic cell transplantation

Non-coding mismatches in HLA Class I genes in the presence of DPB1 mismatches predict worse outcomes in hematopoietic cell transplantation