Promoting Equitable and Affordable Patient Access to Safe and Effective Innovations in Donation and Transplantation of Substances of Human Origin and Derived Therapies.

Innovation is a hallmark of organ, tissue, and cell transplantation. The development of new treatments derived from these substances of human origin (SoHO) has rapidly evolved in recent years. Despite the great benefits that these innovative therapies could bring to patients, significant difficulties have arisen in making them equitably and widely accessible. Herein, we identify and address 4 challenges to promote innovation in this field in a collaborative, sustainable, and transparent manner and propose some concrete solutions applicable to SoHO-derived treatments, ranging from cell therapies to solid organ transplantation. Regulators, health policymakers, and government officials are recommended to incorporate specific elements into the regulatory frameworks of their respective jurisdictions, although regulatory convergence and equivalent quality and safety standards applicable to SoHO at a global level would be needed. An innovation-driven regulatory environment, respectful with the human origin and in accordance with the altruistic donation of SoHO, should be encouraged to improve the safety, effectiveness, accessibility, and affordability of SoHO and to promote collaboration between countries and between public and private sectors. This overview is the outcome of a working group focused on "Innovation in the donation and clinical application of SoHO" as part of the international Summit "Towards Global Convergence in Transplantation: Sufficiency, Transparency and Oversight" convened by the Organización Nacional de Trasplantes under the Spanish Presidency of the Council of the European Union in November 2023 and cosponsored by the Council of Europe, the World Health Organization, the Transplantation Society, and the European Society for Organ Transplantation.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Radiation hazards of the Ukraine nuclear power plants: how can international blood and marrow stem cell transplant societies help?

Any conflict in countries that process nuclear power plants raises concerns of the potential radiation injuries to the people in that region and beyond such as the current conflict in Ukraine. International healthcare organizations and societies should prepare for the potential scenarios of nuclear incidents. The Worldwide Network for Blood and Marrow Transplantation (WBMT) and its members, have recent experience preparing for this type of events such as the Fukushima incident in 2011. In this article, we discuss the risks of radiation exposure, current guidelines, and scientific evidence on hematopoietic support, including the role of hematopoietic stem cell transplant (HCT) for those exposed to nuclear radiation, and the role that the WBMT and other global BMT societies can play in triaging and managing people suffering from radiation injuries.

Endemic or regionally limited bacterial and viral infections in haematopoietic stem-cell transplantation recipients: a Worldwide Network for Blood and Marrow Transplantation (WBMT) Review.

Literature discussing endemic and regionally limited infections in recipients of haematopoietic stem-cell transplantation (HSCT) outside western Europe and North America is scarce. This Worldwide Network for Blood and Marrow Transplantation (WBMT) article is part one of two papers aiming to provide guidance to transplantation centres around the globe regarding infection prevention and treatment, and considerations for transplantation based on current evidence and expert opinion. These recommendations were initially formulated by a core writing team from the WBMT and subsequently underwent multiple revisions by infectious disease experts and HSCT experts. In this paper, we summarise the data and provide recommendations on several endemic and regionally limited viral and bacterial infections, many of which are listed by WHO as neglected tropical diseases, including Dengue, Zika, yellow fever, chikungunya, rabies, brucellosis, melioidosis, and leptospirosis.

Endemic or regionally limited parasitic and fungal infections in haematopoietic stem-cell transplantation recipients: a Worldwide Network for Blood and Marrow Transplantation (WBMT) Review.

There is a scarcity of data on endemic and regionally limited fungal and parasitic infections in recipients of haematopoietic stem-cell transplantation (HSCT) outside western Europe and North America. This Worldwide Network for Blood and Marrow Transplantation (WBMT) Review is one of two papers aiming to provide guidance to transplantation centres worldwide regarding prevention, diagnosis, and treatment based on the currently available evidence and expert opinion. These recommendations were created and reviewed by physicians with expertise in HSCT or infectious disease, representing several infectious disease and HSCT groups and societies. In this paper, we review the literature on several endemic and regionally limited parasitic and fungal infections, some of which are listed as neglected tropical diseases by WHO, including visceral leishmaniasis, Chagas disease, strongyloidiasis, malaria, schistosomiasis, histoplasmosis, blastomycosis, and coccidioidomycosis.

Eye drops of human origin-Current status and future needs: Report on the workshop organized by the ISBT Working Party for Cellular Therapies.

BACKGROUND AND OBJECTIVES: Serum eye drops (SEDs) are used to treat ocular surface disease (OSD) and to promote ocular surface renewal. However, their use and production are not standardized, and several new forms of human eye drops have been developed. MATERIALS AND METHODS: The International Society for Blood Transfusion Working Party (ISBT WP) for Cellular Therapies held a workshop to review the current types of eye drops of human origin (EDHO) status and provide guidance. RESULTS: The ISBT WP for Cellular Therapies introduced the new terminology 'EDHO' to emphasize that these products are analogous to 'medical products of human origin'. This concept encompasses their source (serum, platelet lysate, and cord blood) and the increasingly diverse spectrum of clinical usage in ophthalmology and the need for traceability. The workshop identified the wide variability in EDHO manufacturing, lack of harmonized quality and production standards, distribution issues, reimbursement schemes and regulations. EDHO use and efficacy is established for the treatment of OSD, especially for those refractory to conventional treatments. CONCLUSION: Production and distribution of single-donor donations are cumbersome and complex. The workshop participants agreed that allogeneic EDHO have advantages over autologous EDHO although more data on clinical efficacy and safety are needed. Allogeneic EDHOs enable more efficient production and, when pooled, can provide enhanced standardization for clinical consistency, provided optimal margin of virus safety is ensured. Newer products, including platelet-lysate- and cord-blood-derived EDHO, show promise and benefits over SED, but their safety and efficacy are yet to be fully established. This workshop highlighted the need for harmonization of EDHO standards and guidelines.

An Analysis of the Worldwide Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) has an aggressive course and a historically dismal prognosis. For many patients, hematopoietic stem cell transplantation (HSCT) represents the best option for cure, but access, utilization, and health inequities on a global scale remain poorly elucidated. We wanted to describe patterns of global HSCT use in AML for a better understanding of global access, practices, and unmet needs internationally. Estimates of AML incident cases in 2016 were obtained from the Global Burden of Disease 2019 study. HSCT activities were collected from 2009 to 2016 by the Worldwide Network for Blood and Marrow Transplantation through its member organizations. The primary endpoint was global and regional use (number of HSCT) and utilization of HSCT (number of HSCT/number of incident cases) for AML. Secondary outcomes included trends from 2009 to 2016 in donor type, stem cell source, and remission status at time of HSCT. Global AML incidence has steadily increased, from 102,000 (95% uncertainty interval: 90,200-108,000) in 2009 to 118,000 (104,000-126,000) in 2016 (16.2%). Over the same period, a 54.9% increase from 9659 to 14,965 HSCT/yr was observed globally, driven by an increase in allogeneic (64.9%) with a reduction in autologous (-34.9%) HSCT. Although the highest numbers of HSCT continue to be performed in high-resource regions, the largest increases were seen in resource-constrained regions (94.6% in Africa/East Mediterranean Region [AFR/EMR]; 34.7% in America-Nord Region [AMR-N]). HSCT utilization was skewed toward high-resource regions (in 2016: AMR-N 18.4%, Europe [EUR] 17.9%, South-East Asia/Western Pacific Region [SEAR/WPR] 11.7%, America-South Region [AMR-S] 4.5%, and AFR/EMR 2.8%). For patients <70 years of age, this difference in utilization was widened; AMR-N had the highest allogeneic utilization rate, increasing from 2009 to 2016 (30.6% to 39.9%) with continued low utilization observed in AFR/EMR (1.7% to 2.9%) and AMR-S (3.5% to 5.4%). Across all regions, total HSCT for AML in first complete remission (CR1) increased (from 44.1% to 59.0%). Patterns of donor stem cell source from related versus unrelated donors varied widely by geographic region. SEAR/WPR had a 130.2% increase in related donors from 2009 to 2016, and >95% HSCT donors in AFR/EMR were related; in comparison, AMR-N and EUR have a predilection for unrelated HSCT. Globally, the allogeneic HSCT stem cell source was predominantly peripheral blood (69.7% of total HSCT in 2009 increased to 78.6% in 2016). Autologous HSCT decreased in all regions from 2009 to 2016 except in SEAR/WPR (18.9%). HSCT remains a central curative treatment modality in AML. Allogeneic HSCT for AML is rising globally, but there are marked variations in regional utilization and practices, including types of graft source. Resource-constrained regions have the largest growth in HSCT use, but utilization rates remain low, with a predilection for familial-related donor sources and are typically offered in CR1. Further studies are necessary to elucidate the reasons, including economic factors, to understand and address these health inequalities and improve discrepancies in use of HSCT as a potentially curative treatment globally.

Suitability of haematopoietic cell donors: updated consensus recommendations from the WBMT standing committee on donor issues.

The contribution of related donors to the globally rising number of allogeneic haematopoietic stem cell transplantations (HSCT) remains increasingly important, particularly because of the growing use of haploidentical HSCT. Compared with the strict recommendations on the suitability for unrelated donors, criteria for related donors allow for more discretion and vary between centres. In 2015, the donor outcome committee of the Worldwide Network for Blood and Marrow Transplantation (WBMT) proposed consensus recommendations of suitability criteria for paediatric and adult related donors. This Review provides updates and additions to these recommendations from a panel of experts with global representation, including the WBMT, the European Society for Blood and Marrow Transplantation donor outcome committee, the Center for International Blood and Marrow Transplant Research donor health and safety committee, the US National Marrow Donor Program, and the World Marrow Donor Association, after review of the current literature and guidelines. Sections on the suitability of related donors who would not qualify as unrelated donors have been updated. Sections on communicable diseases, clonal haematopoiesis of indeterminate potential, paediatric aspects including psychological issues, and reporting on serious adverse events have been added. The intention of this Review is to support decision making, with the goal of minimising the medical risk to the donor and protecting the recipient from transmissible diseases.

Increasing access to hematopoietic cell transplantation in Latin America: results of the 2018 LABMT activity survey and trends since 2012.

A total of 5642 hematopoietic cell transplants (HCT) in 5445 patients (2196-40% allogeneic and 3249-60% autologous) were reported by 127 teams in 14 Latin American countries that answered the 2018 LABMT/WBMT Global Transplant Activity survey. The transplant rate (defined as the number of first transplants per 10 million inhabitants per year) was 85 (51 autologous and 34 allogeneic) in 2018. The main indications for allogeneic HCT were acute leukemias (60%), while plasma cell disorders and lymphomas were the most common conditions warranting autologous HCT (50 and 36%, respectively). In the allogeneic HCT, HLA-identical siblings were the main type of donor (44%) followed by related mismatched/haploidentical donors (32%). Peripheral blood stem cells were used in 98% of the autologous and in 64% of the allogeneic transplants. From 2012 to 2018, there was a 64% increase of reported HCT (54% in autologous and 80% in allogeneic). In the allogeneic setting, the most pronounced increase in donor type was observed in haploidentical relatives (from 94 procedures in 2012 up to 710 in 2018), surpassing unrelated donors as of 2017. Significant trends detected in Latin America include rising numbers of the procedures reported, a faster increase in allogeneic HCT compared with autologous HCT and a significant increase in family mismatched/haploidentical donors. The LABMT/WBMT activity survey provides useful data to understand the HCT activity and trends in Latin America.

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.

Worldwide Network for Blood and Marrow Transplantation (WBMT) perspective: the role of biosimilars in hematopoietic cell transplant: current opportunities and challenges in low- and lower-middle income countries.

Health care costs attributed to biologics have increased exponentially in the recent years, thus biosimilars offer a possible solution to limit costs while maintaining safety and efficacy. Reducing expenditure is vital to health care especially in developing countries where affordability and access to health care is a major challenge. We discuss the opportunities and the challenges of biosimilars in the field of hematopoietic cell transplantation (HCT) in low- and lower-middle income countries. Developing countries can potentially invest in the forecasted costs reduction by utilizing biosimilars. This can be used to decrease the costs of procedures such as HCT, which is a rapidly growing field in many developing regions. The introduction of biosimilars in the developing regions faces many challenges which include, but are not limited to: legal and regulatory issues, lack of research infrastructure, and the presence of educational barriers. Thus, collaborative efforts are needed to ensure an effective and safe introduction of biosimilars into low- and lower-middle income countries.

Correction: Worldwide Network for Blood and Marrow Transplantation (WBMT) perspective: the role of biosimilars in hematopoietic cell transplant: current opportunities and challenges in low- and lower-middle income countries.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Production and Quality Requirements of Human Platelet Lysate: A Position Statement from the Working Party on Cellular Therapies of the International Society of Blood Transfusion.

Human platelet lysate (HPL), rich in growth factors, is an efficient alternative supplement to fetal bovine serum (FBS) for ex vivo propagation of stromal cell-based medicinal products. Since 2014, HPL has been a focus of the Working Party for Cellular Therapies of the International Society of Blood Transfusion (ISBT). Currently, as several Good Manufacturing Practice (GMP)-compliant manufacturing protocols exist, an international consensus defining the optimal modes of industrial production, product specification, pathogen safety, and release criteria of this ancillary material (AM) is needed. This opinion article by the ISBT Working Party summarizes the current knowledge on HPL production and proposes recommendations on manufacturing and quality management in line with current technological innovations and regulations of biological products and advanced therapy medicinal products.

A novel simplified method of generating cytomegalovirus-specific cytokine-induced killer cells of high specificity and superior potency with GMP compliance.

We describe a method of rendering polyclonal cytokine-induced killer cells (CIK) specific against cytomegalovirus (CMV), focusing on GMP compliance. Peripheral blood mononuclear cells (PBMNC) are stimulated with pooled CMV peptides pp65 and IE-1 for 16-24 h and the reactive T cell subset which up-regulate CD137 is further co-stimulated with anti-CD137, followed by expansion in G-Rex flasks under standard CIK culture condition. This method generates a large number CMV-specific CIK with superior potency compared to published method currently in clinical trials. The cytotoxicity as measured by chromium release assay correlates with the upregulation of CD107a upon peptide re-challenge as measured by flow cytometry. CMV-CIK at maturity consist of mainly late effector memory CD8 T cells and have a skewed TCR repertoire with preferential expansion of a few families. Such CMV-CIK retain their function after freezing and thawing. CMV-CIK thus generated is ready for clinical trial against drug-resistant CMV disease.