Nonmalignant Hematologic Disorders Research Articles

Real-World Challenges of Haplo-Identical Hematopoietic Stem Cell Transplant in a Developing Country: A Single Center Experience.

Hematopoietic stem cell transplant (HSCT) is potentially, the sole curative option for many malignant and non-malignant hematological disorders. Finding a human leukocyte antigen (HLA) compatible donor remains one of the limiting factors, hampering the utilization of HSCT. However, the introduction of post-transplant cyclophosphamide (PTCy) has improved the outcomes of haploidentical transplants making it a suitable option for patients lacking HLA-compatible donors. We collected data from 44 patients who underwent haplo-identical allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) from the year 2015 to 2022. The diseases were divided into three categories, i.e., bone marrow failure (BMF) syndromes, hematological malignancies (HM) and miscellaneous (Misc) groups. Median age at transplant was 18 (01-39) years. Transplant indications included aplastic anemia (AA) in 21 (47.7%) cases, 15 (34.1%) HM, and eight (18.2%) cases falling in the Misc groups. A maximum number of graft failures occurred in the BMF group; primary graft failure in 07 (33.3%) cases and secondary graft failure in four (19%) cases, (p-value < 0.05). Acute graft versus host disease (aGVHD) grade II-IV occurred in nine (20.5%) cases while chronic graft versus host disease (cGVHD) occurred in 10 (22.7%) cases. Cytomegalovirus (CMV) reactivation was seen in 31 (70.5%) cases. Maximum CMV reactivation was seen in HM group 13 (86.6%) cases, (p-value < 0.05) as compared to BMF (71.4%) and Misc groups (37.5%). Post-transplant cyclophosphamide (PTCy) based regimens, early neutrophil engraftment, and patients with GVHD had better survival outcomes (p-value < 0.05) overall survival (OS), and relapse-free survival (RFS). and GVHD-free relapse-free survival (GFRS) were significantly better in cases with early neutrophil engraftment. OS of the study cohort was 50% while disease-free survival (DFS) and GFRS were 45.5% and 36.4%, respectively.

Recent advancements in hematopoietic stem cell transplantation in Taiwan.

Hematopoietic stem cell transplantation (HSCT) can cure malignant and nonmalignant hematological disorders. From 1983 to 2022, Taiwan performed more than 10,000 HSCT transplants. The Taiwan Blood and Marrow Transplantation Registry collects clinical information to gather everyone's experience and promote the advances of HSCT in Taiwan to gather everyone's experience and promote advances of HSCT in Taiwan. Compared with matched sibling donors, transplants from matched unrelated donors exhibited a trend of superior survival. In Taiwan, transplant donors showed remarkable growth from unrelated (24.8%) and haploidentical (10.5%) donors. The number of older patients (17.4%; aged ≥61 years) who underwent transplantation has increased markedly. This review summarizes several significant developments in HSCT treatment in Taiwan. First, the use of Anti-thymocyte globulin (ATG) and intravenous busulfan regimens were important risk factors for predicting hepatic sinusoidal obstruction syndrome. Second, a new, machine learning-based risk prediction scoring system for posttransplantation lymphoproliferative disorder has identified five risk factors: aplastic anemia, partially mismatched related donors, fludarabine use, ATG use, and acute skin graft-versus-host disease. Third, although the incidence of idiopathic pneumonia syndrome was low (1.1%), its mortality rate was high (58.1%). Fourth, difficult-to-treat mantle cell and T-cell lymphomas treated with autologous HSCT during earlier remission had higher survival rates. Fifth, treatment of incurable multiple myeloma with autologous HSCT showed a median progression-free survival and overall survival of 46.5 and 70.4 months, respectively. Sixth, different haploidentical transplantation strategies were compared. Seventh, caution should be taken in administering allogeneic HSCT treatment in older patients with myeloid leukemia with a Charlson Comorbidity Index ≥3 because of a higher risk of nonrelapse mortality.

Chronic GVHD: review advances in prevention, novel endpoints, and targeted strategies.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many malignant and non-malignant hematologic disorders. Chronic graft-versus-host (cGVHD) disease remains a significant hurdle for long-term survival in patients post allo-HCT, and it remains the leading cause of late non-relapse mortality. The risk factors for development of cGVHD include degree of human leukocyte antigen (HLA) disparity, increasing recipient age, use of peripheral blood stem cells as a source, myeloablative conditioning regimens, prior acute GVHD (aGVHD), and female donor to male recipient. Our biological understanding of cGVHD is mostly derived from transplantation mouse models and patient data. There are three distinct phases in the development of cGVHD. Approaches to prevent GVHD include pharmacologic strategies such as calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mTOR inhibitors (sirolimus), and IMP dehydrogenase inhibitors (mycophenolate mofetil). Increasingly, posttransplant cyclophosphamide is emerging as a promising strategy for GVCHD prevention especially in a setting of reduced intensity conditioning. Other approaches include serotherapy (ATG, Campath) and graft manipulation strategies. A significant obstacle to evaluating the response of novel GVHD-directed therapies has been standardized response assessments. This has functioned as a barrier to designing and interpreting clinical trials that are structured around the treatment of cGVHD. Novel endpoints including failure-free survival, Graft-versus-host disease-free, relapse-free survival (GRFS), and current GVHD-free, relapse-free survival (CGRFS) may create a clearer picture for post-HCT outcomes. Targeted therapies including Bruton's tyrosine kinase inhibition, JAK1/2 inhibition, and ROCK2 inhibitors have improved cGVHD therapy, especially in the steroid refractory setting. Continued improvement in prophylactic strategies for cGVHD, identification of accurate cGVHD treatment endpoints, and access to novel therapeutic agents are expected to improve cGVHD outcomes.

Establishing a Sociodemographic Data Banking Study in Patients with Hematologic Disorders - a Feasibility Assessment

Introduction Social determinants of health (SDOH) play a critical role in patient-related health outcomes. Several small-scale studies among patients with sickle cell disease have demonstrated an association between adverse SDOH and inferior health outcomes-with subsequent calls for SDOH-targeted interventions to improve outcomes. Few studies have investigated the impact of SDOH in other hematologic disorders. Systematic collection of modifiable SDOH data (e.g. transportation, food, utility, and housing insecurity) among patients with non-malignant hematologic disorders is essential to identify populations at risk for disparate outcomes and concurrently inform the design of interventions to mitigate health inequities. Objective To determine the feasibility of establishing a clinically annotated sociodemographic data banking protocol for patients establishing care in the hematology clinic of a tertiary academic pediatric center in the United States. Methods A single-center, prospective, sociodemographic banking study at Dana-Farber / Boston Children's Cancer and Blood Disorders Center opened to accrual in non-malignant hematology in October 2022. Subjects &amp;lt;18 years old within 6 months of a new non-malignant hematologic diagnosis establishing care within the outpatient hematology clinic were considered eligible for the study. The research team (a physician, a research coordinator, and an intern) screened weekly hematology clinic lists to identify eligible patients beginning first with a single disease group (sickle cell disease) and subsequently expanding to include other disease groups (immune thrombocytopenia, thrombosis, iron deficiency anemia) as study support allowed. Patients were approached sequentially, in-person while at a scheduled clinic visit. Parents who consented to the study completed a single time-point survey at study enrollment asking questions about their home environment. Paper/pencil or REDCap surveys available in English and Spanish were self-completed or read aloud by study personnel in any language with an appropriate interpreter. At the time of consent, parents/guardians signed a HIPAA release allowing the study team to track the course of disease-targeted therapy received and associated treatment responses. Survey domains include demographics, household material hardship, household income, social support, resilience, anxiety/depression, and experiences of discrimination. Data were banked for future research studies with appropriate IRB approval. Results A total of 65 eligible patients with a new hematologic diagnosis of sickle cell disease, immune thrombocytopenia, thrombosis, or iron deficiency anemia were approached and offered an opportunity to participate, with 43 (66%) consenting to participation. Among the 22 who declined participation, 10 (46%) declined contact with all research study teams, 6 (27%) transferred care to a satellite clinic, and 6 (27%) declined participation following study introduction. Among consenting participants, 31 (72%) have completed the baseline survey, including n=28 in English and n=3 in Spanish. A total of n=9 surveys are pending and n=3 surveys are considered missing (&amp;gt;8 weeks since consent with survey not yet completed) data. Conclusion Systematic collection of SDOH data for research purposes in the context of a sociodemographic data banking study is feasible in a large, tertiary-care outpatient hematology clinic based on high participant willingness to enroll and complete surveys and successful implementation in four hematologic disease groups. This study will expand to include all hematologic disease groups by late 2023. This protocol has already been implemented successfully among pediatric oncology patients with de novo or relapsed/refractory cancers and those receiving cellular therapy, and is being expanded to 2 additional US institutions. Expanding this protocol to other care centers across the United States will provide essential data to advance health equity research in pediatric hematology/oncology.

The Relationship between Telomere Length and Epigenetic Aging with Hematologic Diseases Risk: A Multivariable Mendelian Randomisation Study

Introduction: Aging is a complex phenomenon that involves multifaceted changes, including significant alterations in telomere length and epigenetic aging. When aging affects the hematopoietic system, it leads to a gradual increase in mutations in hematopoietic stem cells, making individuals more susceptible to the development of hematologic diseases. However, due to the limitations of observational studies, such as potential confounding factors and reverse causality, the precise causal direction and magnitude of the relationship between telomere length, epigenetic aging, and the incidence of hematologic diseases remain uncertain. Therefore, we conducted an investigation to determine the causal relevance of telomere length and epigenetic aging in relation to hematologic diseases using Mendelian randomization (MR). Methods: Firstly, we conducted a 2-sample single-variable Mendelian randomization (SVMR) study to examine the genetically predicted effects of telomere length and epigenetic age acceleration, as measured by HannumAge, Horvath Intrinsic Age, PhenoAge, GrimAge, and DNAm PAI-1 (DNA methylation-estimated plasminogen activator inhibitor-1) levels, on multiple hematologic diseases, including anemia, lymphoma, leukemia, myeloproliferative diseases, and hemostasis and coagulation diseases. Additionally, we used lasso regression to exclude multicollinearity in SNPs and subsequently performed multivariable MR using the screened SNPs to adjust for statistically significant risk factors, and MR Bayesian model averaging was performed to rank the significant risk factors based on their genetic evidence (Figure A). Results: Summary data were available for 19 malignant hematological neoplasms and 35 non-malignant hematological disorders, corresponding to 70,813 cases and 12,253,012 controls. Increased telomere length due to germline genetic variation was generally associated with increased risk for hematologic diseases. The strongest associations were observed for lymphoma, lymphoid leukaemia, Hodgkin lymphoma, chronic lymphocytic leukaemia, essential thrombocythaemia, unspecified types of non-Hodgkin lymphoma, multiple myeloma, Non-follicular lymphoma, unspecified iron deficiency, leukaemia, while higher levels of telomere length was associated with a reduced risk of pernicious anaemia (Figure B). Meta-analyzed IVW MR findings suggested that higher PhenoAge acceleration was associated with increased risks of myeloid leukemia, chronic lymphocytic leukemia, and lymphoid leukemia. Conversely, higher PhenoAge acceleration was linked to reduced risks of unspecified disorders of white blood cells and unspecified coagulation defects. Similarly, SVMR showed genetic predisposition for GrimAge acceleration to be associated with increased risks of amyloidosis, unspecified anemias, and myeloid leukemia. Conversely, genetically predicted GrimAge acceleration was associated with reduced risks of hemorrhagic anemia, hemolytic anemias, and idiopathic thrombocytopenic purpura. Furthermore, our findings suggested that elevated HannumAge acceleration increased the risks of lymphoma, leukemia, and lymphoid leukemia.Conversely, higher HannumAge acceleration was associated with a reduced risk of chronic myeloid leukemia. Additionally, higher levels of DNAm PAI-1 were found to be associated with an increased risk of chronic myeloid leukemia. However, there was no evidence of causality between genetically predicted Intrinsic epigenetic age acceleration and the 19 malignant hematological neoplasms and 35 non-malignant hematological disorders mentioned (Figure C). We utilized MVMR-LASSO to estimate the combined effects of telomere length and five epigenetic clocks on hematologic diseases. After adjusting for epigenetic aging, we observed a significant positive association between telomere length and various hematologic diseases, including leukemia, lymphoid leukemia, chronic lymphocytic leukemia, lymphomas, Hodgkin lymphoma, non-follicular lymphoma, unspecified types of non-Hodgkin lymphoma, essential thrombocythemia, and multiple myeloma (Figure D&amp;E). Conclusion: Longer telomeres and epigenetic aging may increase the risk of developing most hematologic malignancies, while simultaneously raising or decreasing the risk of certain non-malignant hematologic diseases.

Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood

Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.

Busulfan and subsequent malignancy: An evidence-based risk assessment.

The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted. We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3years of follow-up. We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12years. The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.

Bone marrow transplant: A two-decade single centre hematology experience

BackgroundBone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. MethodsWe reviewed our BMT data since the inception of the program till Feb 2023. ResultsOver 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. ConclusionThe evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of “transplant for all”. Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Disturbance in the reconstitution of distinct T-cell subsets and the incidence of GvHD following allo-HSCT in pediatric patients with non-malignant hematological disorders

BackgroundThe reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD. MethodsWe evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor. ResultsCD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD. ConclusionOur findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD.

Pulmonary Histopathologic Findings in Pediatric Patients After Hematopoietic Stem Cell Transplantation: An Autopsy Study.

Pathologic characterization of pulmonary complications following hematopoietic stem cell transplantation (HSCT) is limited. We describe lung findings in pediatric patients who died following HSCT and attempt to identify potential clinical associations. Pathology databases at Texas Children's Hospital and the Children's Hospital of Philadelphia were queried (2013-2018 CHOP and 2017-2018 TCH). Electronic medical records and slides were reviewed. Among 29 patients, 19 received HSCT for hematologic malignancy, 8 for non-malignant hematologic disorders, and 2 for metastatic solid tumors. Twenty-five patients (86%) showed 1 or more patterns of acute and organizing lung injury. Sixty-two percent had microvascular sclerosis, with venous involvement noted in most cases and not correlating with clinical history of pulmonary hypertension, clinical transplant-associated thrombotic microangiopathy, irradiation, or graft-versus-host disease. Features suggestive of graft-versus-host-disease were uncommon: 6 patients had lymphocytic bronchiolitis, and only 2 patients had evidence of bronchiolitis obliterans (both clinically unexpected), both with a mismatched unrelated donor transplant. Acute and subacute alveolar injury (diffuse alveolar damage or organizing pneumonia) is common in pediatric patients who died following HSCT and is difficult to assign to a specific etiology. Microvascular sclerosis was frequent and did not correlate with a single distinct clinical feature.

Paroxysmal nocturnal hemoglobinuria: Where are we going.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare nonmalignant clonal hematological disorder that is characterized by a deficiency of the GPI-linked complement regulators on the membrane of hematopoietic cells, which renders them susceptible to complement-mediated damage. Intravascular hemolysis (IVH), increased tendency for thrombosis, and bone marrow failure constitutes hallmark features of the disease and are associated with high morbidity and mortality. The introduction of C5 inhibitors radically changed disease outcomes, offering a near-normal life expectancy to PNH patients. However, residual IVH and extravascular hemolysis (EVH) continue to occur during C5-inhibitor treatment, leaving a significant proportion of patients' anemic and some remaining transfusion dependent. Quality of life (QoL) has also been an issue with the regular intravenous (IV) administrations of the currently licensed C5 inhibitors. This has led to the exploration and development of novel agents, targeting different parts of the complement cascade, or having different formulations allowing for self-administration. Longer-acting and subcutaneous formulations of C5 inhibitors have shown equal safety and efficacy, whereas the development of proximal complement inhibitors is changing completely the therapeutic landscape of PNH, limiting both IVH and EVH and showing superior efficacy over C5 inhibitors, especially in improving haemoglobin. Combination treatments have also been tested with promising results. This review summarizes the current therapeutic options, gaps in anti-complement therapy and discusses emerging therapeutic approaches for PNH.

Practice harmonization workshops of EBMT: an expert-based approach to generate practical and contemporary guidelines within the arena of hematopoietic cell transplantation and cellular therapy

For hematopoietic cell transplantation (HCT) and cellular therapy (CT), clinical patient care is localized, and practices may differ between countries and from center to center even within the same country. Historically, international guidelines were not always adapted to the changing daily clinical practice and practical topics there were not always addressed. In the absence of well-established guidelines, centers tended to develop local procedures/policies, frequently with limited communication with other centers. To try to harmonize localized clinical practices for malignant and non-malignant hematological disorders within EBMT scope, the practice harmonization and guidelines (PH&G) committee of the EBMT will co-ordinate workshops with topic-specific experts from interested centers. Each workshop will discuss a specific issue and write guidelines/recommendations that practically addresses the topic under review. To provide clear, practical and user-friendly guidelines when international consensus is lacking, the EBMT PH&G committee plans to develop European guidelines by HCT and CT physicians for peers’ use. Here, we define how workshops will be conducted and guidelines/recommendations produced, approved and published. Ultimately, there is an aspiration for some topics, where there is sufficient evidence base to be considered for systematic reviews, which are a more robust and future-proofed basis for guidelines/recommendations than consensus opinion.

CRISPR/Cas9 system in hematopoietic stem cells: Basic research and clinical applications

Clustered regularly interspaced short palindromic repeats (CRISPR) approach adapted from the prokaryotic adaptive immune system against to pathogen attack is so valuable and promising tool for treatment of human malignant and non-malignant hematological disease and disorders through genome editing in hematopoietic stem cells (HSCs). Moreover, CRISPR/Cas9 approach is not only useful for therapeutic purposes; it is considerably preferred for the generation of in vitro and in vivo animal disease models. CRISPR/Cas9 approach has been developed for highly efficient on-target cleavage, and low off-target effect via delivery systems and manipulation of CRISPR components including single guide RNA (sgRNA) and Cas enzymes. In this review, we focused on the CRISPR/Cas9 system applications on hematopoietic stem cells in basic research and clinical area with basic research and clinical perspectives.

Ferumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow Imaging.

Ferumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow Imaging.

Current Trends in Transplantation of Patients with Hematological Malignancies

Hematopoietic stem cell transplantation (HSCT) is widely used to treat hematological malignancies and nonmalignant hematological disorders. Many advances have been made in improving the success of bone marrow transplantation. However, lack of available matched related or matched sibling donors has posed a significant challenges to the availability and proper utilization of hematopoietic stem cell transplantation in patients with hematological malignancies. The rising availability of alternative donors, particularly haploidentical donors (HIDs), has propelled the rapid rise of allo-HSCT. The aim of this review is to highlight and evaluate the recent advances in the development of HSCT, focusing mainly on the selection of suitable hematopoietic stem cell donors, HID-HSCT and some current advances in the use of umbilical cord blood cells as an alternative graft source. Haplo-HSCT has shown a promising result and better outcomes due to the number of advantages, including a wide range of stem cell sources, increased GVL effects, improved immunologic reconstitution, and positive clinical outcomes. In the near future, haplo-HSCT is likely to be considered as a better option for patient donor selection particularly in AML patients while HLA matching is unlikely to be the most important factor in AML patient donor selection. In addition, the use of umbilical cord blood cells has shown a promising role as an alternative source of HSCT even with other available sources such as bone marrow and peripheral blood. Other transplantation procedures, such as T-cell depletion allografts, Post-transplant cyclophosphamide (PTCY), G-CSF-mobilized allografts, and antithymocyte globulin, have contributed to significant improvements in haplo-HSCT outcomes in recent decades.

Analysis of anti-SARS-CoV-2 IgG antibody titers after mRNA booster vaccination in patients with nonmalignant hematological disorders

In our facility, anti-SARS-CoV-2 mRNA vaccines were given to 21 patients, including 8 with aplastic anemia (AA), 3 with pure red cell aplasia (PRCA), and 10 with immune thrombocytopenic purpura (ITP), and IgG antibody titers were assessed one month after vaccinations. After receiving both a second vaccine and a booster shot, all patients with AA/PRCA treated with cyclosporine A aside from one, had IgG titers that were lower than the median levels of healthy controls. Even if prednisolone (PSL) doses did not go over 10 mg/day, ITP patients receiving PSL therapy were unable to achieve adequate levels of IgG after booster immunizations.

S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice

AbstractAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1−/− and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.

Addressing Clinical Management Challenges in the Treatment of Rare, Non-Malignant Hematologic Disorders through Educational Interventions

BACKGROUND: Despite continuous progress, the management of rare, non-malignant hematologic disorders is still fraught with challenges, including delays in diagnosis, a paucity of targeted therapies and treatment guidelines, suboptimal clinical outcomes, limited clinical trials, and access to information and support. To improve competence in navigating some of these challenges and incorporate patient perspectives in treatment selection, educational initiatives focusing on three rare hematologic disorders were designed in collaboration with the National Organization for Rare Disorders (NORD). METHODS: As part of the Second Annual Rare Cancers and Blood Disorders series, three CME activities on AL amyloidosis (60 minutes), paroxysmal nocturnal hemoglobinuria (PNH) (30 minutes), and cold agglutinin disease (CAD) (30 minutes) were broadcast on OMedLive in April 2022 and remain on-demand through April 2023. A 90-minute complementary PNH program was broadcast live-online on OMedLive in May 2022 and remains on-demand through May 2023. All programs were led by expert hematologists in each subject area. Live programs featured an interactive panel of physicians and live Q&A. Additionally, the 90-minute PNH program featured patient vignettes to elevate clinicians' awareness of patient experiences. For each program, knowledge and competence questions were administered pre-, immediate post-, and 2 months post-activity. Provider-reported barriers and challenges managing patients with rare blood disorders, and intent to modify treatment plans post-program were also assessed. RESULTS: As of July 13th, 2022, 297 clinicians have participated in these activities, 92% of whom are physicians, advanced practitioners (NP/PA), and nurses. Sixty percent of clinicians see between 1 and 10 patients each week with any of these rare disorders (AL, CAD, or PNH). CME questions administered across all programs revealed low baseline knowledge and competence as shown in Table 1. Following the educational activities, improvements ranging from 19% to 59% were seen for pre/post paired responses across all CME questions. Limited knowledge about clinical presentation and differential diagnoses were noted as the top barriers to diagnosis of all three disorders. The greatest challenges in managing patients were identified as "time to diagnosis" for AL amyloidosis and PNH and "lack of novel therapies" for CAD; and most clinicians (41%) perceived "adhering to treatment schedules" as the greatest treatment-related challenge faced by patients. Ninety-four percent of clinicians were motivated to modify treatment plans according to their patients' treatment response. Qualitative and 2-month follow-up data on clinical practice change and impact on patient outcomes will be shared. CONCLUSIONS: Online education on rare, non-malignant hematologic disorders improves clinician knowledge of evidence-based management strategies, uncovers persistent gaps in barriers to care, and stimulates clinical practice change that incorporates patient perspectives, leading to better patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Nanoparticles targeting hematopoietic stem and progenitor cells: Multimodal carriers for the treatment of hematological diseases.

Modern-day hematopoietic stem cell (HSC) therapies, such as gene therapy, modify autologous HSCs prior to re-infusion into myelo-conditioned patients and hold great promise for treatment of hematological disorders. While this approach has been successful in numerous clinical trials, it relies on transplantation of ex vivo modified patient HSCs, which presents several limitations. It is a costly and time-consuming procedure, which includes only few patients so far, and ex vivo culturing negatively impacts on the viability and stem cell-properties of HSCs. If viral vectors are used, this carries the additional risk of insertional mutagenesis. A therapy delivered to HSCs in vivo, with minimal disturbance of the HSC niche, could offer great opportunities for novel treatments that aim to reverse disease symptoms for hematopoietic disorders and could bring safe, effective and affordable genetic therapies to all parts of the world. However, substantial unmet needs exist with respect to the in vivo delivery of therapeutics to HSCs. In the last decade, in particular with the development of gene editing technologies such as CRISPR/Cas9, nanoparticles (NPs) have become an emerging platform to facilitate the manipulation of cells and organs. By employing surface modification strategies, different types of NPs can be designed to target specific tissues and cell types in vivo. HSCs are particularly difficult to target due to the lack of unique cell surface markers that can be utilized for cell-specific delivery of therapeutics, and their shielded localization in the bone marrow (BM). Recent advances in NP technology and genetic engineering have resulted in the development of advanced nanocarriers that can deliver therapeutics and imaging agents to hematopoietic stem- and progenitor cells (HSPCs) in the BM niche. In this review we provide a comprehensive overview of NP-based approaches targeting HSPCs to control and monitor HSPC activity in vitro and in vivo, and we discuss the potential of NPs for the treatment of malignant and non-malignant hematological disorders, with a specific focus on the delivery of gene editing tools.

The evolution of fertility preservation care models in a large pediatric cancer and blood disorders center.

Children and adolescents who receive gonadotoxic treatments are at risk for future infertility. While there is a growing focus on integrating fertility preservation (FP) within pediatric cancer and blood disorder centers, wide variations in care models and methods exist across institutions. The purpose of this work is to describe the evolution of FP care models within a large pediatric hematology/oncology center. Models of care and associated timeframes are described, including a pre-FP program model, establishment of a formal FP program, integration of nurse navigators, and the addition of FP consult stratification based on urgency (urgent/nonurgent). The number of patient consults within each model, patient sex, diagnosis (oncologic/hematologic), and consult timing (pre-gonadotoxic treatment/posttreatment completion) were abstracted from the clinical database. The number of annual consults increased from 24 during the pre-FP program model (2015) to 181 during the current care model (2020). Over time, the proportion of consults for females and patients with nonmalignant hematologic disorders increased. Patient stratification reduced the proportion of consults needing to be completed urgently from 75% at the advent of the FP program to 49% in the current model. The evolution of care models within our FP program allowed for growth in the number of consults completed, expansion of services to more patients with nonmalignant hematologic disorders, and more consults for female patients. Nurse navigators play a critical role in care facilitating referrals, coordination, and patient education. Urgency stratification has allowed FP team members to manage increasing FP-related encounters.