Hematopoietic Transplantation Research Articles

Repeatability of Quantitative Magnetic Resonance Imaging Biomarkers in the Tibia Bone Marrow of a Murine Myelofibrosis Model.

Quantitative MRI biomarkers are sought to replace painful and invasive sequential bone-marrow biopsies routinely used for myelofibrosis (MF) cancer monitoring and treatment assessment. Repeatability of MRI-based quantitative imaging biomarker (QIB) measurements was investigated for apparent diffusion coefficient (ADC), proton density fat fraction (PDFF), and magnetization transfer ratio (MTR) in a JAK2 V617F hematopoietic transplant model of MF. Repeatability coefficients (RCs) were determined for three defined tibia bone-marrow sections (2-9 mm; 10-12 mm; and 12.5-13.5 mm from the knee joint) across 15 diseased mice from 20-37 test-retest pairs. Scans were performed on consecutive days every two weeks for a period of 10 weeks starting 3-4 weeks after transplant. The mean RC with (95% confidence interval (CI)) for these sections, respectively, were for ADC: 0.037 (0.031, 0.050), 0.087 (0.069, 0.116), and 0.030 (0.022, 0.044) μm2/ms; for PDFF: 1.6 (1.3, 2.0), 15.5 (12.5, 20.2), and 25.5 (12.0, 33.0)%; and for MTR: 0.16 (0.14, 0.19), 0.11 (0.09, 0.15), and 0.09 (0.08, 0.15). Change-trend analysis of these QIBs identified a dynamic section within the mid-tibial bone marrow in which confident changes (exceeding RC) could be observed after a four-week interval between scans across all measured MRI-based QIBs. Our results demonstrate the capability to derive quantitative imaging metrics from mouse tibia bone marrow for monitoring significant longitudinal MF changes.

Cellular Therapies: Yesterday, Today, and Tomorrow.

Cellular therapy (CT) can be defined as the transference into a person of healthy cells to correct defective functions. Yesterday (1950-2010), CT consisted mostly of hematopoietic transplants for the treatment of a variety of hematological disorders. Interestingly, during that period of time other cell types with therapeutic potential-including certain lymphoid populations and other nonhematopoietic cells-were discovered and characterized; thus, CT became a promising discipline for the treatment of a broader diversity of diseases. Today (2011-2023), CT has significantly grownup through preclinical studies and clinical trials, and it is currently progressing toward its consolidation as one of the pillars of medicine in the 21st century. Indeed, different types of stem cells (e.g., hematopoietic, mesenchymal, neural, and pluripotent), as well as different lymphoid and myeloid cell populations (e.g., TILs, CAR-Ts, CAR-NKs, and DUOC-01) are being used in clinical settings or are being tested in clinical trials. For the past decade, several CT modalities have been developed, and today, many of them are being used in the clinic. Tomorrow (2024-2040), already established CT modalities will surely be improved and applied more frequently, and novel therapies (that will include cell types such as iPSCs) will enter and expand within the clinical ground. It is noteworthy, however, that despite significant advancements and achievements, problems still need to be solved and obstacles need to be overcome. Technical, ethical, and economic issues persist and they need to be addressed. Undoubtedly, exciting times of challenges and opportunities are coming ahead in the CT arena.

Glanzmann Thrombasthenia: A Curse to Platelet Function

A platelet function disorder that is autosomal recessive with altered platelet number and appearance is called Glanzmann thrombasthenia. Quantitative and qualitative abnormalities of αIIbβ3 integrin are the molecular basis of this condition. Adhesive proteins attach aggregating platelets under the influence of this receptor and result in thrombus formation at the location of injury in blood vessels. Some patients have minimum bruising, while others have severe and frequent fatal hemorrhages in GT. Its common symptoms include purpura, epistaxis, menorrhagia, or gastrointestinal bleeding. Both alleles of one of the genes that code for the platelet integrin receptor polypeptides are affected by mutations, which results in the disease. Chronic anemia, neurological problems, and psychological problems are complications associated with this condition. Platelet aggregation, complete blood count, and prothrombin time are the standard tests to diagnose Glanzmann's thrombasthenia. Antifibrinolytics, platelet transfusions, monoclonal antibodies, hematopoietic stem molecular transplantation, and gene remedy are interventions to deal with this uncommon hematological disorder. If the treatment measures are ineffective, or to prevent bleeding during surgery, then transfuse HLA-compatible platelet concentrates. Recombinant Factor VIIa is used as an alternative therapy for this condition. Implementation of appropriate preventive measures helps us to keep this disorder at bay.

Donor derived hematopoietic stem cell niche transplantation facilitates mixed chimerism mediated donor specific tolerance.

Compelling experimental evidence confirms that the robustness and longevity of mixed chimerism (MC) relies on the persistence and availability of donor-derived hematopoietic stem cell (HSC) niches in recipients. Based on our prior work in rodent vascularized composite allotransplantation (VCA) models, we hypothesize that the vascularized bone components in VCA bearing donor HSC niches, thus may provide a unique biologic opportunity to facilitate stable MC and transplant tolerance. In this study, by utilizing a series of rodent VCA models we demonstrated that donor HSC niches in the vascularized bone facilitate persistent multilineage hematopoietic chimerism in transplant recipients and promote donor-specific tolerance without harsh myeloablation. In addition, the transplanted donor HSC niches in VCA facilitated the donor HSC niches seeding to the recipient bone marrow compartment and contributed to the maintenance and homeostasis of stable MC. Moreover, this study provided evidences that chimeric thymus plays a role in MC-mediated transplant tolerance through a mechanism of thymic central deletion. Mechanistic insights from our study could lead to the use of vascularized donor bone with pre-engrafted HSC niches as a safe, complementary strategy to induce robust and stable MC-mediated tolerance in VCA or solid organ transplantation recipients.

Improved Vδ2+ T cells recovery correlates to reduced incidences of mortality and relapse in acute myeloid leukemia after hematopoietic transplantation.

Acute myeloid leukemia (AML) patients can benefit from allogeneic hematopoietic cell transplantation (alloHCT) and achieve long-term remission. Recovery of T cell quantity and quality is critical to reduce the incidences of life-threatening complications after alloHCT. Although the general recovery level of γδ T cells is recognized to be associated with outcomes of patients who suffered from various hematological diseases and received alloHCT, the correlation between γδ T cell subsets and the prognosis in AML patients following transplantation remains to be investigated. In the current study, the recoveries of T cell subpopulations in 103 AML patients were dissected at different time points after haploidentical HCT (haploHCT). Statistical analyses showed that the absolute number of Vδ2+ T cells on day 90 was an independent risk factor for predicting 2-year OS in AML patients following haploHCT. The survival advantage from the improved recovery of day-90 Vδ2+ T cells was attributed to reducing the infection-related mortality. Consistently, lower 2-year non-relapse mortality was found in recipients with higher day-90 levels of Vδ2+ T cells. Notably, day-270 Vδ2+ T cell numbers reversely correlated to both 2-year and 5-year probabilities of relapse in this scenario. These results highlighted the significant correlation of Vδ2+ T cells recovery with long-term survival and relapse after alloHCT, suggesting that Vδ2+ T cells-based immune strategies may help control infectious complications and leukemia recurrence in AML patients.

Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir.

There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV-specific T-cell reconstitution in allogeneic hematopoietic transplant recipients (allo-HSCT) undergoing letermovir (LMV) prophylaxis. Twelve adult CMV-seropositive high-risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non-LMV allo-HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real-time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500IU/ml. CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo-HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV-specific T-cell expansion in a single CMV-seropositive donor were also conducted. Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non-LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non-LMV patients exhibiting detectable CMV-specific T-cell responses was comparable (7/10 vs. 10/13; p=.71). Nevertheless, median CMV-specific CD4+ and CD8+ T-cell counts were lower in LMV patients by days +60 (p=.006 and .02, respectively) and +90 (p=.08 and .02). Ex vivo, CMV-specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%). In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV-specific T-cell reconstitution in LMV patients compared to non-LMV patients was observed.

Non-Aspergillus Hyaline Molds: A Host-Based Perspective of Emerging Pathogenic Fungi Causing Sinopulmonary Diseases.

The incidence of invasive sino-pulmonary diseases due to non-Aspergillus hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: Fusarium spp., Scedosporium spp., Lomentospora prolificans, Scopulariopsis spp., Trichoderma spp., Acremonium spp., Paecilomyces variotii, Purpureocillium lilacinum, Rasamsonia argillacea species complex, Arthrographis kalrae, and Penicillium species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.

Nursing training: Self-care in patients undergoing hematopoietic stem cell transplantation in a specialized oncologic institution [Entrenamiento enfermería: Autocuidado en pacientes sometidos a trasplante de progenitores hematopoyéticos en una institución especializada oncológica

Self-care in post-transplanted patients of hematopoietic progenitors at home is transcendental to improve their health conditions. The purpose of the educational activity on self-care is to establish communicative strategies to improve their situation, reducing preventable post-transplant complications and avoiding constant readmissions. The personalized counseling provided by the nurse to the patient and family members improves their quality of life. Objectives: To determine the level of self-care of patients undergoing hematopoietic progenitor transplantation in a specialized oncologic institution, 2022. Methodology: quantitative, descriptive, non-experimental, cross-sectional design. The population consisted of 108 patients attending the TAMO service, the type of sampling was probabilistic. An instrument with 2 dimensions of self-care was applied: knowledge and skills with 30 items with a Likert scale. The instrument was validated with a Cronbach's alpha of 0.8. The results show that 100% of the patients have adequate self-care. In relation to the dimensions: knowledge 94.4%, in skills 87% presented high levels respectively. It is concluded that continuing nursing education maintains solvency in self-care in the patient's daily life.

330 - Glutathione Reductase, Oxidative Stress and Survival after Hematopoietic Stem Transplant

330 - Glutathione Reductase, Oxidative Stress and Survival after Hematopoietic Stem Transplant

Improved efficacy of mesenchymal stromal cells stably expressing CXCR4 and IL-10 in a xenogeneic graft versus host disease mouse model.

Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. In vitro experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF-1α and also improved their immunomodulatory properties compared to unmodified Ad-MSCs (WT-MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3+-IL10+ cells), and increased the number of regulatory T and B cells. Our in vitro and in vivo studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.

191 - Protracted Diarrhea from High-Dose Melphalan in Autologous Hematopoietic Transplantation: Response to Short Course of Oral Budesonide

191 - Protracted Diarrhea from High-Dose Melphalan in Autologous Hematopoietic Transplantation: Response to Short Course of Oral Budesonide

449 - Long-Term Follow-up Outcomes of Patients That Underwent Allogeneic or Autologous Hematopoietic Transplant Shortly after a COVID-19 Infection

449 - Long-Term Follow-up Outcomes of Patients That Underwent Allogeneic or Autologous Hematopoietic Transplant Shortly after a COVID-19 Infection

525 - A case of atypical inflammatory myopathy in a 4-year-$$$old girl after hematopoietic bone marrow transplantation

525 - A case of atypical inflammatory myopathy in a 4-year-$$$old girl after hematopoietic bone marrow transplantation

The aging of the immune system and its implications for transplantation.

By the last third of life, most mammals, including humans, exhibit a decline in immune cell numbers, immune organ structure, and immune defense of the organism, commonly known as immunosenescence. This decline leads to clinical manifestations of increased susceptibility to infections, particularly those caused by emerging and reemerging microorganisms, which can reach staggering levels-infection with SARS-CoV-2 has been 270-fold more lethal to older adults over 80years of age, compared to their 18-39-year-old counterparts. However, while this would be expected to be beneficial to situations where hyporeactivity of the immune system may be desirable, this is not always the case. Here, we discuss the cellular and molecular underpinnings of immunosenescence as they pertain to outcomes of solid organ and hematopoietic transplantation.

Autologous hematopoietic bone marrow and concentrated growth factor transplantation combined with core decompression in patients with avascular necrosis of the femoral head.

The study aimed to assess the effectiveness of autologous hematopoietic bone marrow and concentrated growth factor (CGF) transplantation and core decompression in patients with avascular necrosis of the femoral head (ANFH). We performed a single-center prospective study on 31 patients with non-traumatic early-stage (stage I to III) ANFH based on the 1994 classification of the Association Research Circulation Osseous (ARCO). The patients were subjected to bone marrow aspiration from the posterior iliac crest, separation, and concentration of growth factors from the bone marrow aspirate, core decompression of the femoral head, and injection of hematopoietic bone marrow and CGFs into the necrotic lesion. Patients were evaluated using the visual analogue scale, the WOMAC questionnaire, and X-ray and MRI examinations of the hip joints before, at 2, 4, and 6 months after the intervention. Patients had a mean age of 33 years (range 20-44 years), 19 (61%) of them being male and 12 (39%) females. The presentation of the disease was bilateral in 21 patients and unilateral in 10 patients. The main cause of ANFH was steroid treatment. The mean VAS and WOMAC scores were 48.37 (SD: 14.67) out of 100, and the mean VAS pain score was 50.83 out of 100 (SD: 20.46), respectively, before transplant. This value significantly improved to 22.31 (SD 12.12) of 100, and the mean VAS pain score was 21.31 of 100 (SD: 20.46) (P=0.04). MRI showed a significant improvement (P=0.012). Our results suggest that autologous hematopoietic bone marrow and CGFs transplantation with core decompression have a beneficial effect in early-stage ANFH.

Sirolimus as immunosuppressive agent in pediatric allogenic hematopoetic transplant recipients

Sirolimus as immunosuppressive agent in pediatric allogenic hematopoetic transplant recipients

Evaluating the effectiveness of a training program to support nurses to administer cryopreserved hematopoietic stem cells by intravenous push method.

A training program was developed to prepare registered nurses (RNs) at one cellular therapy centre to administer cryopreserved cells by intravenous (IV) push method. There are two main methods of infusion for dimethyl sulfoxide (DMSO) cryopreserved hematopoietic stem cell (HSC) products, gravity drip and IV push. Administering DMSO by either route can cause hypersensitivity reactions. Administration of HSCs by gravity drip is slower, resulting in fewer DMSO reactions. However, prolonged exposure of DMSO once the cells are thawed increases the risk of cellular damage. The faster IV push method reduces cell damage and decreases staff time. An environmental review within Canadian transplant centres found that in most adult centres, nurses administer by gravity drip, and when IV push is required, cryopreserved hematopoietic stem cells are administered by physicians. Our centre's method was IV push by a physician or nurse practitioner (NP). As transplant numbers grew, capacity to perform this skill needed to expand. To maintain the current benefits of the IV push method and increase capacity in a hematopoietic transplant program, the role of infusing stem cells by the IV push method was transitioned from the NPs and physicians to RNs. A successful training program utilizing simulation to support these oncology nurses in learning the new skill was developed and evaluated.

A systematic review evaluating the efficacy of autologous hematopoietic transplantation for diffuse large B cell lymphoma-type Richter syndrome.

Chronic lymphocytic leukemia (CLL) can transform into fast growing lymphoma for diffuse large B-cell lymphoma (DLBCL) called Richter's syndrome (RS), which is commonly related to an existence of large B-cells with equal or larger size than macrophage nuclei or more than twice those of normal lymphocyte. We conducted a systematic review of the existing literature to assess the clinical efficacy of auto-HCT for patients with RS. We searched 4 main databases; EMBASE, Google Scholar, Scopus, PubMed and Web of Science and was done on December 26, 2021. All analyses in this study were performed by Stata software and this review was reported in accordance with PRISMA 2020. Data was extracted from 4 articles; the total number of patients was reported to be 110. Based on the meta-analysis findings, pooled overall survival rate was 56.36% (95%CI= (46.98-65.31). In figure 2, the forest plot of combined results is shown. Despite the use of common treatment regimens such as chemo immunotherapy and the availability of novel therapies including B-cell receptor inhibitors and rituximab-cyclophosphamide-hydroxydaunorubicin-Oncovin-prednisone (CHOP-R) regimen, the status of disease progression and recovery in RS cases is still not strong enough.

2119. Predictive Value of the Immunodeficiency Scoring Index for COVID-19 Related Outcomes in Hematopoietic Transplant Recipients

Abstract Background The Coronavirus Disease 2019 (COVID-19) has significantly impacted cancer patients with some reported mortality as high as 25%. The Immunodeficiency Scoring Index (ISI) was developed as a prognostic tool in allogeneic hematopoietic cell transplant (allo-HCT) recipients with respiratory syncytial virus but also for other respiratory viruses to predict severe infections and mortality. The purpose of our study was to correlate the ISI in HCT recipients with COVID-19 and associated complications such as hospitalization, supplemental oxygen use, and mortality. Methods We performed a cohort study of HCT recipients of all ages with COVID-19 between March 2020 and October 2021. We included only patients who were diagnosed by a PCR-based assay. We excluded patients for whom an ISI score, as previously described, could not be calculated. Outcomes of interest included 60-day mortality, hospital and ICU admission due to COVID-19, and supplemental oxygen requirements. A univariate analysis using Fischer exact testing for nominal variables was performed. Results Out of the 219 HCT with COVID-19, 101 were excluded due to alternative methods of diagnosis (13), lack of laboratory values needed to calculate an ISI at time of COVID-19 diagnosis (79), or COVID-19 diagnosed prior to transplant (9). Out of the remaining 118 patients, the median age was 60 years (range 6-85), most were male (56%), Caucasian (57%), and had no smoking history (64%). Most patients had an alloHCT (66%) with matched related donor [MRD] (25%), or matched unrelated donor [MUD] (21%) (Table 1). Median time from transplant to COVID-19 was 615 days (range 2-5692), median ISI was 3 (range 0-11), and 92% of patients were unvaccinated prior to COVID-19 (Table 1). On univariate analysis, an ISI of moderate to high (score ≥3) was associated with COVID-19 related hospitalization [p=0.0147] and an ISI ≥ 4 was associated with 60-day all-cause (p=0.045) and COVID-19-related (p-0.019) mortality (Table 2). Table 1: Patient Characteristics Abbreviations: Hematopoietic Cell Transplant (HCT); Chronic Obstructive Pulmonary Disease (COPD); Chronic Kidney Disease (CKD); End-Stage Renal Disease (ESRD); Acute Lymphocytic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML) Myeloproliferative Disorder (MDS); Matched Related Donor (MRD); Matched Unrelated Donor (MUD); Mismatched Unrelated Donor (MMUD); Graft versus Host Disease (GvHD); Lower Respiratory Tract Infection (LRI); White Blood Cell (WBC); Absolute Neutrophil Count (ANC); Absolute Lymphocyte Count (ALC). Table 2: Univariate Analysis of Outcomes due to COVID-19 in HCT Recipients Abbreviations: Immunodeficiency Scoring Index (ISI); Hematopoietic Cell Transplant (HCT); Allogenic (Allo); Autologous (Auto); Lower Respiratory Infection (LRI); High-Flow Nasal Cannula (HFNC) Figure 1: Survival Curve (Kaplan-Meier Curve) Comparing Time to Death in Patients with an ISI Score of 4 or Greater. (Log-rank 0.0295) Conclusion An ISI of 4 or greater was a prognostic marker for worse outcomes such as COVID-related and all-cause mortality in HCT recipients. Whether an aggressive and prompt management of high-risk patients with COVID-19 may impact these outcomes needs to be determined in future studies. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Enrichment of innate immune cells from PBMC followed by triple cytokine activation for adoptive immunotherapy.

Innate immune cells [Natural killer (NK) and gamma-delta (γδ) T-cells] have the advantage of mediating graft versus leukemia (GVL) without graft versus host disease (GVHD). Therefore, the infusion of activated innate immune cells post allogenic hematopoietic stem transplant (AHSCT) is a promising adoptive immunotherapy strategy for relapsed and/or refractory myeloid malignancies. Microbead depletion of T-cells and B-cells has been used as a graft manipulation method to prevent GVHD post haploidentical AHSCT. These grafts are enriched for NK and γδ T-cell receptor (TCR+) cells. Brief ex vivo activation of purified NK cells with interleukin (IL)-12, IL-18, and IL-15 [triple cytokines (TC)] has been shown to produce cells with a memory like function and significantly enhanced leukemia cytotoxicity. In our studies we depleted αβ TCR+ and CD19+ B-cells from healthy donors' peripheral blood mononuclear cells (PBMC) using microbeads; enriching the frequency of NK and γδ TCR+ cells. Following overnight TC incubation, we observed that these innate immune cells were activated based on phenotypic expression of CD69 and CD25. Further, we observed increased cytotoxicity of TC activated innate immune cells against NK sensitive and NK refractory leukemic cell targets. Further, the presence or absence of monocytes did not alter activation marker expression or in vitro cytotoxicity of innate immune cells. Additionally, we observed correlation between target cytotoxicity and mature activated NK phenotypes (CD56dim or CD56dim with co-expression of the activation markers CD69+ and/or CD25+). This approach of depleting T- and B-cells from PBMCs, combined with overnight TC activation, provides a novel cell population for donor lymphocyte infusion (DLI) post AHSCT.