The human placenta is a transient yet crucial organ that plays a key role in sustaining the relationship between the maternal and fetal organisms. Despite its historical classification as "biowaste," placental tissues have garnered increasing attention since the early 1900s for their significant medical potential, particularly in wound repair and surgical application. As ethical considerations regarding human placental derivatives have largely been assuaged in many countries, they have gained significant attention due to their versatile applications in various biomedical fields, such as biomedical engineering, regenerative medicine, and pharmacology. Moreover, there is a substantial trend toward various animal product substitutions in laboratory research with human placental derivatives, reflecting a broader commitment to advancing ethical and sustainable research methodologies. This review provides a comprehensive examination of the current applications of human placental derivatives, explores the mechanisms behind their therapeutic effects, and outlines the future potential and directions of this rapidly advancing field.

Over the past three decades, advancements in collection methods for hematopoietic stem cell transplantation substantially reduced invasiveness and safety concerns. To what extent, however, registered donors are informed about extraction methods and how their beliefs drive their willingness to follow through with a donation is not well understood. Inaccurate beliefs about extraction methods may cause donors to overestimate their perceived cost, potentially reducing donations. In a survey with about 24,000 potential donors in Germany's largest stem-cell registry, we investigate how beliefs about extraction methods affect potential donors' willingness to follow through with a stem cell donation. We find widespread misconceptions about extraction methods, with many donors attributing a significant fraction of stem cell extractions to be coming from never-used methods. Importantly, a lack of knowledge and misconceptions about extraction methods persist among registered donors, often anchored to methods that prevailed at the time of registration. Exploring the link between donors' beliefs and their (stated) willingness to donate, we find that accurate beliefs about lower extraction costs correlate with a 2.2-2.9 percentage points higher willingness to donate, representing a 40% reduction in donor unavailability. Our results highlight the need for informational campaigns to correct donors' misconceptions and potentially save more lives among blood cancer patients.

High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www.clinicaltrials.gov as #NCT03983850.

Although allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a lifesaving therapy for patients with hematologic malignancies, only 30% of patients in need of transplantation will have a human leukocyte antigen matched related donor available.

This article introduces an approved alternative donor stem cell source that is shown to provide earlier engraftment and decreased infections compared to dual or single umbilical cord blood transplantation.

This article provides an overview of the pathophysiology, clinical trial results, and nursing management of the approved omidubicel-onlv cellular therapy product as an alternative donor source for patients undergoing alloHSCT.

Omidubicel provides an alternative donor source for patients undergoing alloHSCT for whom there is no matched donor available. This need may be particularly great in ethnic and racial minority populations who may be underrepresented in the NMDP BioTherapies database.

Acute myeloid leukemia (AML) presents a significant global health challenge due to its aggressive behavior and mortality rates. Traditionally, AML treatment has relied on intensive chemotherapy-anthracyclines and cytarabine. However, recent breakthroughs in targeted therapies are transforming clinical practices. This review examines current treatment strategies, including breakthrough therapies. Also, a global perspective on AML management includes the disparity in treatment availability, particularly the difficulties faced by low- and middle-income countries due to the high cost and restricted access to novel therapies.

In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 patients with CMV seropositivity who received unrelated allo-HCT. We divided the entire cohort into 2 cohorts according to the donor CMV serostatus: CMV positive (DP) and negative (DN). We also stratified each cohort into 4 groups based on donor age (aged ≥40 or <40 years) and HLA parity (8/8 or 7/8): Young88 and Old88, and Young78 and Old78, respectively. In the CMV-DP cohort, the Old88 (hazard ratio [HR], 1.20; P = .012), Young78 (HR, 1.35; P < .001), and Old78 (HR, 1.60; P < .001) groups were associated with inferior overall survival (OS) than the Young88 group. In contrast, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP: HR, 1.19; P = .001; CMV-DN: HR, 1.04; P = .53; P for interaction, .070), as was the impact of HLA (CMV-DP: HR, 1.34; P < .001; CMV-DN: HR, 1.08; P = .23; P for interaction, .012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.

Patients of racial minorities have lower chance of securing a suitable donor, essential part of successful allogeneic stem cell transplant. In this simulated interview study, we sought to examine how hematologists discuss donor options and risks with patients with high-risk myeloid neoplasm considering transplant. Thirty-seven US hematologists participated (65% male; 65% white, 24% Asian, none Black), randomly assigned to meet with a Black or white patient actor. The hematologists emphasized the benefits of a full match with the white patient and high chance of securing a donor. Conversely, with the Black patient, they tended not to ask about ancestry, discuss the donor registry, race implications or challenges with donor search. Knowing the patient had children, many recommended haploidentical transplant. The unique circumstances of transplant argue for a focused communication including discussing race. While conversations should be tailored to each patient, limiting essential information on donor options may contribute to disparities.

Profiling the HLA diversity at the population level benefits multiple clinical and anthropological applications, such as tracing population migration, identifying genetic relationships between different groups, quantifying the added diversity in a global donor pool and matching for solid organ and stem cell transplantation. We calculated nine-locus HLA-A ∼ C ∼ B ∼ DRB1 ∼ DRB3/4/5 ∼ DQA1 ∼ DQB1 ∼ DPA1 ∼ DPB1 allele and haplotype frequencies in about 170,000 volunteer donor genotypes from the NMDP Mexico (NMDP MX, previously Be The Match Mexico) donor center. These donors are predominantly of Mexican ancestry recruited from multiple regions in Mexico. The goal of the study was to describe the HLA genetic profiles of the Mexican population and investigate the contribution of these donors' HLA in serving Mexican, US and international patients in need of hematopoietic cell transplants. Additionally, we estimated that almost all Mexican patients will have an available 5 of 8 or better matched donor in the NMDP MX donor center with matches also available for some of the Latino patients in the U.S. We demonstrate that Mexican populations clustered genetically and shared multiple frequent alleles and haplotypes with populations from the US Mexican or Chicano, US South/Central American Hispanic, and some Latino populations. Operationally, 78 % of NMDP Mexico donors contributed genotypes that were observed a total of three times or less on the registry, increasing the diversity of the overall NMDP registry. More than 300 donor collections were facilitated through the NMDP MX donor center serving mostly Hispanic/Latino patients in the US and abroad. This study highlights the importance of adding the NMDP MX donors to the worldwide donor pool and paves the way for a data-driven strategy for future planning and donor recruitment.

While the World Marrow Donor Association global database currently offers approximately 42.7 million potential donors and cord blood units to patients in need of haematopoietic cell transplant, lack of eight HLA-matched donors remains a significant barrier. The Registry of Unmet Need (RUN) Project seeks to address disparities in transplant access for patients with rare HLA genotypes, particularly those from populations that have been historically underrepresented and underserved by global donor registries. Patients eligible for this study searched for an unrelated donor for transplant between 2015 and 2017 and, at that time, lacked a potential eight-of-eight HLA-matched unrelated donor (MUD). Sixteen donor registries contributed data from 3654 patients using standardised data-collection project templates. To address this unmet need, pooled data were analysed to identify trends and inform global recruitment strategies. Patient genotypes were queried against the global inventory at later timepoints in 2018 and 2023 to determine whether potential matches had been recruited within the years since the initial search. Patient haplotypes were imputed using an open-source method referencing US population frequencies. The imputation process used five continental reference populations and 21 detailed populations derived from the NMDP database. The method provided a Bayesian inference of population membership. A control group consisting of US patients that yielded 1000 or more potential matches was used for comparison. RUN patient haplotype and genotype frequencies were substantially lower compared with controls; both the more frequent and less frequent haplotypes in RUN patients were found to be approximately 100 times less common than those in the control group. We identified 782 potential cases in which a potential MUD was recruited after the initial RUN patient search was performed; while this result is being further investigated, clear patterns of where these new matches can be found have emerged; typically, new matches are found outside the country where the patient search was initiated. Our findings demonstrate that rare haplotypes are the primary barrier to identifying a MUD; the presence of rare alleles or haplotype combinations, as with multi-race ancestry, is rarely the cause. Although strategic donor recruitment efforts will help improve MUD access, patient transplants should not be delayed in pursuit of a MUD when viable alternative options are available.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using TCR αβ+/CD19+ depletion provides an alternative treatment for patients with high-risk (HR) leukemias without a matched donor, especially in developing nations with limited donor registries. We present the outcomes of 36 patients <16 years with HR leukemia who underwent haplo-HSCT with TCR αβ + /CD19 + depletion between 2018 and 2022 at a referral center in Peru. Survival probabilities and cumulative incidence functions were calculated using the Kaplan-Meier method. Patients were followed for a median of 17.38 months (range: 2.34 to 60.36 mo). The 5-year overall survival (OS), 5-year event-free survival (EFS), and non-relapse mortality rates were 72.1%, 72.2%, and 16.7%, respectively. The incidence of relapse for the entire group was 11.1%. Acute graft versus host disease (GvHD) was observed in 36.1% of the patients, with only 2.8% experiencing grade III-IV acute GvHD. No patients developed chronic GvHD. Among all patients, CMV reactivations were observed in 27.78%, HHV-6 reactivations in 33.33%, and ADV or BK virus reactivations in 16.67%. Our study suggests that haplo-HSCT with TCR αβ+/CD19+ depletion is a safe and effective treatment for HR pediatric leukemias. Adopting this approach in major transplant centers throughout the country could improve outcomes for this group of patients.

This meta-analysis assesses the efficacy of TCRαβ+/CD19+ depleted hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematological malignancies, bridging the gap in the heterogeneous results of published studies. We analyzed post-HSCT complications and survival outcomes in 1068 children across 14 studies, using both aggregated and patient-level data from acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and acute lymphoblastic leukemia (ALL) studies, employing the IPDfromKM technique for time-to-event data reconstruction. The analysis reveals a 95 % engraftment success rate (95 % CI: 93-97) and 6-year overall survival and disease-free survival (DFS) rates of 67.2 % and 66.3 %, respectively, with no significant differences in DFS between haploidentical and unrelated donors (hazard ratio = 0.9, 95 % CI: 0.53-1.55). Acute graft-versus-host disease (GvHD) grades III-IV and chronic GvHD incidences were 8 % (95 % CI: 6-11) and 17 % (95 % CI: 10-27). The relapse rate was 27 % (95 % CI: 21-33), with relapse-related mortality at 21 % (95 % CI: 15-28) and HSCT-related mortality at 12 % (95 % CI: 7-19). Relapse was significantly lower in patients (mostly ALL) receiving total body irradiation (risk ratio = 0.53, P = 0.04). These findings underscore TCRαβ/CD19-depleted HSCT as a valuable option for patients without HLA-matched donors, highlighting the need for larger, multicenter studies.

The landscape of acute lymphoblastic leukemia (ALL) treatment is rapidly evolving, with new therapies challenging traditional treatment paradigms. While allogeneic hematopoietic cell transplantation (allo-HCT) remains essential for many high-risk patients, advances in measurable residual disease (MRD) monitoring and the increasing use of immunotherapies in earlier treatment lines have reshaped transplant decision-making. Improvements in donor availability, conditioning strategies, and post-transplant care have expanded access and improved survival, yet relapse and toxicity remain major challenges. This review examines the evolving role of allo-HCT in ALL, highlighting key advancements and ongoing challenges.

Posttransplant high-dose cyclophosphamide (PTCy) is effective in overcoming the negative impact of HLA disparity in the haploidentical setting. In light of these results, we investigated the efficacy of PTCy, in improving clinical outcomes of hematopoietic stem cell transplantation (HSCT) from a mismatched unrelated donor (MMUD) in patients with acute myeloid malignancies by reducing the incidence and severity of acute graft-versus-host disease (aGVHD). A prospective, single-arm, phase 2 study (PHYLOS) was conducted by the Gruppo Italiano Trapianto di Midollo Osseo. The ethical committees of the participating centers approved the study (EURODRACT 2017-003530-85). A total of 77 consecutive patients (acute myeloid leukemia: 64; myelodysplastic syndrome: 13) were enrolled at 26 Italian transplant centers (January 2020-November 2022). Median age of the patients was 53 (range, 19-65) years. The 100-day cumulative incidence of grades 2 to 4 aGVHD was 18.2% (95% CI, 10.6-27.6) and of grades 3 to 4 was 6.5% (95% CI, 3.1-15.1). Seventy-one patients (92%) had full-donor chimerism with complete neutrophil engraftment by day +30. One-year cumulative incidence of chronic GVHD was 13.4% (95% CI, 6.9-22.1). One-year cumulative incidence of nonrelapse mortality was 9.1% (95% CI, 4.0-16.9), and the relapse rate was 23.8% (95% CI, 14.9-33.9). One-year overall survival and graft relapse-free survival were 78.6% (95% CI, 67.4-86.3) and 55.3% (95% CI, 43.4-65.7), respectively. Our study in a homogeneous patient cohort suggests that PTCy leads to a low rate of aGVHD and improves clinical outcomes of HSCT from MMUD. This trial was registered at www.clinicaltrials.gov as #NCT03270748.

While hematopoietic stem cell transplantation is commonly associated with stem cell procedures in public discourse, "stem cell" remains a broad classification. More precise terminology such as "blood stem cell transplantation", "bone marrow transplantation", or "bone marrow stem cell transplantation" may better characterize hematopoietic stem cell procedures in both public and academic contexts. This study aimed to evaluate public comprehension of these specific terms and to assess awareness and attitudes toward stem cell donation, with particular focus on rural populations.

The study recruited 250 participants aged 19-60 years from rural Aksu District, Antalya Province. Individuals with a history of stem cell transplantation, those with a first-degree relative with a history of stem cell transplantation, and healthcare professionals were excluded from the study. The participants were asked 11 questions about their approach to stem cell donation and their thoughts on the subject.

Among the 250 participants, 51.6% (n=129) expressed willingness to become stem cell donors, whereas 48.4% (n=121) reported no willingness to be a donor. Interestingly, 95.6% (n=239) of the participants stated that they would like to know the identity of the person to whom they would be donating stem cells.

This study underscores the need to revisit current anonymity regulations in stem cell transplantation, particularly when both donor and recipient express a desire for mutual identification. Updating regulatory protocols and codes to facilitate information exchange in such cases might be better. Moreover, if the recipient may require further donations from the same donor, the donor should be consulted pre-transplantation about their willingness to provide further support. Their preferences should also be considered in the treatment approach when necessary.

Omidubicel-onlv is an FDA-approved, nicotinamide-modified, allogeneic hematopoietic progenitor cell therapy derived from umbilical cord blood (UCB). A phase 3 study demonstrated improved hematopoietic recovery and decreased infections with omidubicel compared with UCB allogeneic transplantation. We report results of an Expanded Access Program evaluating clinical outcomes in patients with hematologic malignancies following transplantation with omidubicel. Between August 2020 and May 2023, 29 patients were transplanted at 5 US sites. Patients received myeloablative conditioning, prophylactic and therapeutic medications, and supportive care per institutional guidelines, and were monitored for engraftment, infections, and graft-versus-host-disease (GVHD) for up to 2 years post-transplant. Results were compared with previously reported phase 3 outcomes. Omidubicel recipients had a median age of 39 (range 20-73, 62% male); 45% were non-White and 65.5% had acute leukemia. Median follow-up was 11.8 (range: .3-27.7) months. Median neutrophil and platelet engraftment times were 12 and 33.5 days, respectively. Acute GVHD (grade 3-4) at day 100 occurred in 19% of patients, with chronic GVHD at 1 year in 9% of patients, all of which were mild. First grade 2 to 3 bacterial infections through 100 days post-transplant and first grade 3 viral infection 1 year post-transplant occurred in 18% and 12% of patients, respectively. One-year disease-free survival and overall survival rates were 76% and 87%, respectively. This real-world study of omidubicel transplantation for hematologic malignancies finds that this graft source is commonly used for non-White allogeneic transplant recipients. The rapid engraftment kinetics observed following transplantation with omidubicel appears to have addressed excessive nonrelapse mortality that has been previously observed following myeloablative umbilical cord blood transplantation.

Melphalan is often used as the backbone agent for conditioning prior to A/B-T-cell depleted (A/B-TCD) hematopoietic cell transplant (HCT) due to lower rates of organ toxicity compared to busulfan or total-body irradiation, albeit with significant mucosal injury. Traditional dosing based on body-surface-area (BSA) may result in non-optimal melphalan exposure among certain patient subsets.

As mucosal injury is linked to initiation of alloreactivity, we hypothesized that high exposure of melphalan predicted via a pharmacokinetic (PK) model would be associated with an increased risk of acute graft-versus-host disease (aGVHD).

We performed an analysis of 85 patients who underwent A/B-TCD haploidentical HCT on 2 prospective trials using melphalan-based conditioning for treatment of malignancy at 3 centers from 2015 to 2024. Most patients (61.2%) received a total dose of melphalan at 140 mg/m2 using actual body weight; others received a dose adjusted for obesity or age <2 years. We analyzed outcomes based on whether melphalan exposure was above or below the median exposure for the group.

The 100-day cumulative incidences of engraftment syndrome (ES), grade II-IV aGVHD, and grade III-IV aGVHD were 34.2%, 24.8%, and 17.1%, respectively. The 3-year cumulative incidence of chronic GVHD (cGVHD), non-relapse mortality (NRM), and relapse were 17.5%, 8.7%, 21.8%, respectively. The 3-year cumulative incidence of disease-free survival (DFS) and severe GVHD-relapse-free survival (GRFS) were 71.4% and 55.6%, respectively. ES was significantly associated with the subsequent development of aGVHD, both grade II-IV (41.4% vs. 17.3% in those with and without ES, P = .01) and grade III-IV (34.5% vs. 8.5% in those with and without ES; P = .003). Chronic GVHD occurred at significantly higher rates in patients with prior Grade II-IV (66.7% vs. 0% for Grade 0-I; P < .001) and Grade III-IV aGVHD (75% vs. 4.3% for Grade 0-II; P < .001). Compared to non-obese patients, the PK model predicted lower melphalan exposure (P = .02) in obese patients where adjusted ideal body weight was utilized, suggesting overcorrection of the dose. There was no impact of melphalan exposure on immunologic rejection. The median melphalan exposure was 6.81 mg*hr/L (range, 4.4-8.8). Compared to a melphalan exposure ≤6.8 mg*hr/L, a melphalan exposure >6.8 mg*hr/L was associated with a higher incidence of ES (48.8% vs. 19.1%; P = .005), grade II-IV aGVHD (39.3% vs. 10.1%; P = .002), and grade III-IV aGVHD (31.5% vs. 2.5%; P < .001). The 3-year incidence of cGVHD was 27.2% in those with high predicted melphalan exposure compared to 7.4% for low exposure (P = .03); with no difference in 3-year NRM incidence (9.2% vs. 7.7%; P = .82) or 3-year relapse incidence (16.8% vs. 27.6%; P = .31) for high compared to low exposure. However, GRFS was significantly worse in patients with high exposure (46.4%) vs. low exposure (64.6%; P = .02).

High melphalan exposure predicted by a validated population PK model is associated with an increased likelihood of developing ES and subsequently acute and chronic GVHD. Given that a substantial number of patients already require adjustment of standard BSA-based dosing for young age or obesity, a prospective trial of model-based dosing to individualize melphalan exposure is warranted to confirm these results.

Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.

Allogeneic transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5-null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs engraft and reconstitute multiple hematopoietic lineages in vivo and can be engineered to express multiple antibodies simultaneously (in pre-clinical models). Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro. This work lays the foundation for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.

Sickle cell disease (SCD) is the most common hemoglobinopathy in North America. The life expectancy of SCD has extended into adulthood with screenings, preventative care, and hydroxyurea. However, comorbidities arise as adults with SCD age, leading to early mortality.

We conducted a retrospective chart review of the Georgia Comprehensive Sickle Cell Center at Grady Health System, analyzing records of deceased SCD patients from 2013 to 2020.

Amongst the 72 patients analysed, majority had severe complications from SCD and at least 1 cardiovascular comorbidity. The median age of death was 44 (STD = 15.5) for all genotypes with the median age of death at 39 (STD = 14.26) for SS and Sβ0 genotypes (n = 51). There was no difference in the median age of death for patients who maintained regular clinic visits (a visit in the last 6 months prior to death) compared to those who did not. Despite hydroxyurea's known benefits in reducing SCD morbidity and mortality, less than 50% of patients had a prescription.

As new therapies are approved, their impact on SCD-related morbidity and mortality must be evaluated. Improving access to, and education about, disease-modifying therapies like hydroxyurea for both patients and clinicians is essential to improving outcomes.

Chronic graft-versus-host disease (cGVHD) occurs in approximately 1 in 5 pediatric allogeneic HCT patients and is a leading cause of late morbidity and mortality. Late effects of hematopoietic cell transplantation (HCT) may lead to long-term chronic health conditions and shortened life expectancy. In addition to direct physiologic challenges from cGVHD and other late effects, numerous patient-important outcomes impact the quality of life (QOL) of patients and their families. The Research and Education towards Solutions for Late Effects to Innovate, Excel, and Nurture (RESILIENT) after GVHD Consensus Conference was convened to better understand the overlap of cGVHD and late effects in pediatric HCT survivors. Working Committee IV: Patient Important Outcomes identified 4 key areas for focus: (1) What are the key mental health and QOL concerns of survivors of pediatric cGVHD? (2) What is the impact of cGVHD on cognitive performance and social development? (3) What multilevel social determinants of health impact cGVHD survivors, families, and communities? (4) What is the role of racial, ethnic, and socioeconomic factors on the development of cGVHD and the risk for adverse outcomes related to survivorship? For each focus area, the Working Committee reviewed the current state of the field, developed recommendations for clinical practice, and highlighted areas to prioritize for future research. Eleven recommendations were adapted and approved. Substantial overlap exists between the role of cGVHD and late effects on the QOL and mental health of childhood HCT survivors. Recommendations based on available data and consensus opinion may be helpful to improve outcomes for these patients. However, several gaps remain that need further study.

Hematopoietic stem cell expansion relies on direct cell-cell interactions mediated by adhesion molecules, integrins, and cytokines. Unrestricted somatic stem cells have emerged as novel stromal cells supporting hematopoietic stem cell expansion in co-culture conditions via secretion of hematopoiesis-related cytokines and the expression of adhesion molecules. Previous research showed fibrin increased hematopoiesis-related gene expression in these cells. This study focused on the adhesive characteristics of unrestricted somatic stem cells on 3D fibrin scaffolds.

Unrestricted somatic stem cells were isolated from umbilical cord blood and characterized using flow cytometry and multilineage differentiation assays. Scanning electron microscopy and DAPI staining were employed to analyze cell attachment to fibrin. Viability on fibrin was assessed through MTT assays. Quantitative polymerase chain reaction was conducted to evaluate the expression of intercellular adhesion molecule 1 (ICAM-1), integrin subunit αv (ITGAV), and integrin subunit β3 (ITGB3) in cells cultured on 3D fibrin scaffolds.

Cells were positive for CD73, CD105, and CD166 but negative for CD45. Alizarin red and Oil red O stains confirmed calcium deposition and lipid vacuoles. MTT assays revealed that fibrin positively impacts viability. ITGAV expression was significantly increased in cells cultured on fibrin compared to those cultured on plastic tissue culture plates (Control Group). Furthermore, ITGB3 expression showed no significant change in both groups, while ICAM-1 expression was downregulated in cells cultured on fibrin.

Our study revealed that fibrin has a positive impact on the expression of ITGAV, which plays a crucial role in direct cell-cell interactions affecting hematopoietic stem cell expansion.

In recent years, haploidentical hematopoietic stem cell transplantation (haploHSCT) with post-transplant cyclophosphamide (PTCy) has become increasingly prevalent. However, the precise impact of invasive fungal disease (IFD) in relation to graft-versus-host disease (GVHD) prophylaxis and donor type remains to be elucidated.

In this study, we analyzed data from 580 HSCT patients, comprising 80 patients who received haploidentical grafts and 500 patients who received grafts from other donor types. PTCy was exclusively administered to haploidentical HSCT recipients, while cyclosporine A (CsA) in combination with short-course methotrexate (scMTX) was used for patients receiving grafts from other donors.

The IFD rate by PTCy and CsA plus scMTX was 15 % and 15.6 %, respectively. At 6 months and 1 year post-transplant, the cumulative incidence of IFD was 9.4 % and 14.8 % for the PTCy group, and 7.9 % and 12.3 % for the CsA plus scMTX group, respectively. Both groups exhibited poor survival outcomes associated with IFD. Identified risk factors for IFD included age ≥ 45 years, disease relapse, and grade III-IV acute GVHD. Aspergillus spp. and Candida spp. were the most commonly isolated pathogens. High rate of cytomegalovirus reactivation was also noticed in PTCy or CsA plus scMTX group, but not a risk factor for IFD.

The similar IFD rate between haploHSCT with PTCy and others with CsA plus scMTX was documented, with Aspergillus spp. and Candida spp. as the most common pathogens. Further research is needed to investigate IFD following haploHSCT with PTCy and to explore differences with other types of allogeneic HSCT.

Umbilical cord blood (UCB) and matched unrelated donors (MUD) are common alternative donor options in children with high-risk acute myeloid leukemia (AML). Emerging evidence suggests an augmented graft-versus-leukemia (GVL) effect of UCB, but uncertainties persist due to the heterogeneity of the hematopoietic cell transplantation (HCT) characteristics in the previous studies. We reviewed 1148 patients aged ≤18 years with AML, who underwent the first HCT between 2008 to 2017, using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry data. Multivariable analyses evaluated predictors of DFS and other clinical outcomes, factoring in graft source, conditioning regimen, patient age, cytogenetic risk, and HCT year (significance at P < .01). Residual disease status was assessed both as a covariate and as a stratifying factor. Additionally, the differential effects of conditioning regimens were analyzed specifically within the UCB cohort. UCB was used most frequently (33.8%) followed by MUD (29.1%), both of which had comparable DFS and overall survival. In patients with minimal residual disease or not in remission prior to HCT, human-leukocyte antigen (HLA) ≤5/8 matched UCB was associated with lower relapse rates than MUD (hazard risk [HR]: 0.25 and 0.29, P = .005 and .006, respectively) but with increased nonrelapse mortality (HR: 32.8 and 7.5, P = .001 and .012, respectively). Conditioning regimens varies by graft type; total body irradiation (TBI)-based regimens, primarily combined with cyclophosphamide and fludarabine, were more common in the UCB cohort (45% in UCB versus 19% in the other grafts, P < .001). Within the 388 patients received UCB, multivariable analysis demonstrated comparable DFS and OS across variable busulfan- and TBI-based regimens, with no trend of superiority for either approach. In conclusion, highly HLA-mismatched UCB reduced relapse in pediatric AML with higher disease burden but increased nonrelapse mortality, resulting in similar DFS to MUD. Improved supportive care and toxicity mitigation may improve the outcomes of UCB transplant. Overall, UCB should be considered a viable alternative graft source with equally favorable outcomes to MUD. Further research is warranted to refine conditioning regimen, including TBI- and busulfan-based strategies, mitigate toxicity, and improve supportive care to optimize UCB HCT outcomes.

Sickle cell disease (SCD) is a hereditary hemolytic anemia associated with the alteration of the membrane composition of the sickle erythrocytes, the loss of glycolysis, dysregulation of the pyruvate phosphatase pathway, and changes in nucleotide metabolism of the sickle red blood cell (RBC). This review provides a comprehensive overview of the impact of the presence of Hb S, which leads to the disruption of the normal RBC metabolism. The intricate interplay between the redox and energetic balance in erythrocytic cells, where the glycolysis, pentose phosphate pathway, and methemoglobin reductase pathways are all altered in sickle RBC, is a key focus. Moreover, this review summarizes the current knowledge about the disease-modifying agents and their action mechanisms based on the sickle RBC alterations previously mentioned (i.e., their association with beneficial effects on the sickle cells' membrane, to their RBCs' energy metabolism, and to their oxidative status). Therefore, providing a comprehensive understanding of how sickle cells cope with the disruption of metabolic homeostasis and the most promising therapeutic agents able to ameliorate the various consequences of abnormal sickle RBC alterations.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly used treatment for hematologic malignancies. Although posttransplant cyclophosphamide (PtCy) has improved graft-versus-host disease (GVHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. Interferon gamma and interleukin-6 are central in the pathophysiology of GVHD and cytokine release syndrome (CRS), and both cytokines signal through Janus kinase 1 (JAK-1). We tested the effect of adding the JAK-1 selective inhibitor, itacitinib, to PtCy-haplo-HCT to mitigate these complications and improve overall survival (OS). This open-label, single-arm study evaluated the safety and efficacy of itacitinib combined with standard GVHD prophylaxis after haplo-HCT. A total of 42 patients were treated with itacitinib 200 mg daily from day -3 through +100 or +180, followed by a taper. Itacitinib resulted in low CRS grades, all patients had grade 0 (22%) or grade 1 (78%) CRS and there were no cases of grade 2 to 5 CRS. There were no cases of primary graft failure. No patients developed grade 3 to 4 acute GVHD (aGVHD) through day +180. The cumulative incidence of grade 2 aGVHD at day +100 was 21.9%. The 1-year cumulative incidence of moderate or severe chronic GVHD was 5%. The cumulative incidence of relapse at 2 years was 14%. OS at 1 year was 80%. The cumulative incidence of nonrelapse mortality (NRM) at day 180 was 8%. Itacitinib, when added to standard GVHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GVHD, and NRM, and encouraging rates of GVHD-free relapse-free survival and OS after haplo-HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03755414.

One of the most successful treatments in hematologic cancer is chimeric antigen receptor (CAR)-T cell-based immunotherapy. However, CAR-T therapy is not without challenges like the costly manufacturing process required to personalize each treatment for individual patients or graft-versus-host disease. Umbilical cord blood (UCB) has been most commonly used for hematopoietic cell transplant as it offers several advantages, including its rich source of hematopoietic stem cells, lower risk of graft-versus-host disease, and easier matching for recipients due to less stringent HLA requirements compared to bone marrow or peripheral blood stem cells. In this review, we have discussed the advantages and disadvantages of different CAR-T cell manufacturing strategies with the use of allogeneic and autologous peripheral blood cells. We compare them to the UCB approach and discuss ongoing pre-clinical and clinical trials in the field. Finally, we propose a cord blood bank as a readily available source of CAR-T cells.

Healthcare disparities persist in the USA, with Black patients often receiving lower-quality care. Effective doctor-patient communication is crucial for influencing satisfaction, adherence to treatment, and overall health outcomes. This study examined racial disparities in doctor-patient communication, focusing on encounters with Black and White patients recently diagnosed with myelodysplastic neoplasm (MDS). Thirty-seven oncologists participated in simulated encounters with trained actors portraying either Black or White patients. Using an innovative approach combining the comparison of communication characteristics, thematic content, and linguistic analyses, we observed significant disparities in time allocation, linguistic complexity, and relation-building efforts. Encounters with Black patients were notably shorter, with doctors using fewer words per sentence, asking fewer questions, and employing less inclusive and optimistic language. Doctors also had less thorough discussions about transplant options and used fewer words communicating authenticity when talking with Black patients. The post-encounter surveys revealed that doctors were not aware of their shortcomings when interacting with Black patients. The findings provide important insights for the development of training programs aimed at improving healthcare outcomes for marginalized communities and reducing racial healthcare disparities.

Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2 years after biologic assignment to a donor or no donor (SOC) arm based on the availability of an HLA-matched sibling or unrelated donor (BMT CTN 1503). A donor search was commenced after eligibility confirmation. The primary end point was a comparison of survival between the treatment arms 2 years after biologic assignment. Power calculations required 60 participants in the donor arm and 140 in the no donor arm to determine if early transplant-related mortality might be balanced by disease-related mortality over a longer period of follow-up. Secondary objectives were a comparison of the changes in SCD-related events, functional outcomes, and organ function. The data were analyzed according to the intent-to-treat principle. A total of 113 participants were enrolled with 28 in the donor arm and 85 in the no donor arm. The 2-year probabilities of survival were 89% and 93%, in the donor vs no donor arms. Vaso-occlusive pain (VOC) was less frequent in the donor arm in the second year after biologic assignment (P < .001). Based on PROMIS-57 surveys, there was a decrease in fatigue (P = .003) and an increase in the ability to participate in social roles and activities (P = .003) in the donor arm 2 years after biologic assignment. Differences in other secondary outcomes did not reach statistical significance. Barriers to accrual prevented an objective comparison of survival. Assignment to the donor arm led to improvements in VOC, fatigue, and social function. This trial was registered at www.clinicaltrials.gov as #NCT02766465.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by immune dysregulation. Hematopoietic stem cell transplantation (HSCT) represents the only option for long-term cure for primary HLH. However, only around 25% of patients have a fully HLA-matched donor.

In this retrospective study, we analyzed 42 pediatric patients with primary HLH who underwent haplo-SCT using the modified granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol. The conditioning regimen included 300-600 mg/m2 etoposide (VP16), along with low doses of busulfan (Bu) (0.8-1.2 mg/kg every 6 hours on Days -8 to -6), cyclophosphamide (Cy) (10 mg/kg/day on Days -4 to -3), fludarabine (Flu) (30 mg/m2/day on Days -5 to -3), and ATG (8-9 mg/kg total dose on Days -5 to -2) to reduce complications.

All 42 patients achieved successful engraftment. Following a median follow-up period of 48.7 months, 32 of the 42 patients remained alive and disease free. The 2-year overall survival (OS) rate was 78.4%, and the 5-year OS rate was 73.7%. The 2-year failure-free survival (FFS) rate was 71.3%, and the 5-year FFS rate was 66.5%. Patients who achieved complete remission at the time of HSCT showed better OS (p < 0.05). The incidence of Grade III-IV acute graft-versus-host disease (GVHD) was 26.2%, and severe chronic GVHD was observed in 11.9% of patients. Thrombotic microangiopathy occurred in 13 patients, and veno-occlusive disease in two patients.

This modified G-CSF/ATG-based haploidentical protocol demonstrates significant potential for pediatric patients with primary HLH, exhibiting commendable effectiveness and safety.

Retrospective studies suggested that haploidentical transplantation combined with unrelated cord blood might improve survival for patients with haematological malignancies. We aimed to assess whether transplantation of haploidentical peripheral blood stem cells (PBSCs) plus unrelated cord blood would achieve superior disease-free survival compared with transplantation of haploidentical PBSCs plus bone marrow in this population.

We did an open-label, randomised, phase 3 trial at seven hospitals in China. Eligible patients (aged 18-65 years) had a diagnosis of haematological malignancy, an Eastern Cooperative Oncology Group performance status of 0-2 and transplant comorbidity index of 0-2, and were receiving their first allogenic haematopoietic stem cell transplant. Patients were randomly assigned (1:1) to receive transplantation of haploidentical PBSCs plus bone marrow or haploidentical PBSCs plus unrelated cord blood. The primary endpoint was 1-year disease-free survival. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT05290545) and is complete.

Between March 5, 2022, and Jan 2, 2023, 357 participants were screened for eligibility, and 314 were randomly assigned to receive transplantation of haploidentical PBSCs plus unrelated cord blood (n=157) or haploidentical PBSCs plus bone marrow (n=157). Median follow-up was 17·2 months (IQR 10·0-20·8) after random assignment. 1-year disease-free survival was 82·2% (95% CI 75·2-87·3) in the group receiving haploidentical PBSCs plus unrelated cord blood (PBSCs plus unrelated cord blood group) and 65·6% (57·6-72·5) in the group receiving haploidentical PBSCs plus bone marrow ([PBSCs plus bone marrow group] hazard ratio [HR] 0·47, 95% CI 0·30-0·74; p=0·0010). The most common grade 3-5 adverse events within 100 days of transplantation in participants in the PBSCs plus unrelated cord blood and PBSCs plus bone marrow groups were infections (58 [37%] of 157 vs 77 [49%] of 157, p=0·030), acute graft-versus-host disease (49 [31%] vs 61 [39%]), and gastrointestinal disorders (38 [24%] vs 38 [24%]). Seven (4%) patients in the PBSCs plus unrelated cord blood group and 17 (11%) in the PBSCs plus bone marrow group died of transplantation-related causes within 100 days of transplantation. Causes of deaths in the PBSCs plus unrelated cord blood group versus the PBSCs plus bone marrow group included infections (four [3%] vs 11 [7%]), acute graft-versus-host disease (one [1%] vs three [2%]), vascular disorders (two [1%] vs one [1%]), cardiac disorders (none vs one [1%]), and respiratory disorders (none vs one [1%]).

Transplantation of haploidentical PBSCs plus unrelated cord blood achieved superior 1-year disease-free survival compared with transplantation of haploidentical PBSCs plus bone marrow in patients with haematological malignancies, with a more satisfactory safety profile. Our results suggest that combining haploidentical PBSCs with unrelated cord blood, rather than with bone marrow, could be a better treatment option for this population.

None.

Sickle cell disease (SCD) remains associated with reduced life expectancy and poor quality of life despite improvements observed in the last decades mostly related to comprehensive care, use of hydroxycarbamide, screening to identify patients at risk of strokes, and implementation of safe transfusion protocols. The course of the disease is highly variable, making it difficult to predict severity and response to therapy. Allogeneic hematopoietic stem cell transplantation potentially provides a cure with a relatively low rate of complications, but few patients have an HLA-identical sibling. The hopes of patients and healthcare providers have been raised after the initial excellent results of gene therapy studies. However, there is a strong contrast between the high expectations of families and patients and the limited availability of the product, which is technically complex and very expensive. In light of this consideration and of the limited data available on the long-term efficacy and toxicity of different gene therapy approaches, the European Hematology Association Red Cell & Iron Specialized Working Group (EHA SWG) and the hemoglobinopathy working part of the European Blood & Marrow Transplant (EBMT) Group have prioritized the development of recommendations for selection of patients with SCD who are good candidates for gene therapy. The decision-making algorithm was developed by a panel of experts in hemoglobinopathies and/or transplantation chosen by EHA SWG and EBMT, to discuss the selection of SCD patients for gene therapy and draw notes on the related clinical problems.