Half a century of healing: celebrating the 50th anniversary of EBMT.

Introduction

EBMT is a non-profit organization founded in the 1970s when bone marrow transplantation was still in its infancy.

EBMT ( www.ebmt.org ) has a clear mission: “to save the lives of patients with blood cancers and other life-threatening diseases by advancing the fields of blood and marrow transplantation and cell therapy worldwide through science, education and advocacy”.

Early period: the pioneers

Initial enthusiasm for clinical bone marrow transplantation (BMT) had waned following the discouraging outcomes detailed by Bortin in his compendium of 203 bone marrow transplant cases reported between 1959 and 1962, with very few subsequent case reports. Fortunately, not all the pioneers gave up [ 1 ]. Some returned to their labs and forged ahead, developing animal models and attempting clinical transplants using total body irradiation (TBI) conditioning and HLA identical sibling donors.

One of these pioneers was George Mathé, from France. In 1958, Mathé performed BMT on a few accidently irradiated Yugoslavian physicists, becoming the first to attempt human allogeneic BMT and to clinically demonstrate that donor cells survive and propagate only when the recipient’s immune system has been neutralized [ 2 ]. Later, he used TBI followed by a mixture of blood and marrow from six related donors to a patient with chronic myeloid leukemia (CML) in blast crisis. The patient achieved complete remission with full chimerism from one of these donors but, unfortunately, the patient developed graft versus host disease (GVHD) and died from herpes zoster infection 2 years after BMT [ 3 ]. Mathé was also the first to observe that the administration of anti-thymocyte globulin (ATG) and bone marrow infusion led to clinical improvement in some patients, even though engraftment was transient [ 4 ]. This observation led Bruno Speck to propose ATG treatment for patients with severe aplastic anemia [ 5 ].

During this period, several investigators deeply worked to develop animal models and investigate transplant biology. They wanted to understand the obstacles encountered in human BMT and learn how to overcome them. In 1958, Dausset was the first to describe human leucocyte antigens (HLA) and the role of HLA compatibility in organ and bone marrow transplantation [ 6 ]. van Bekkum (Rotterdam/Leiden) used a primate animal model [ 7 ] and Fliedner (Ulm) a dog model to study BMT after radiation exposure [ 8 ]. Thomas and Storb also developed a dog model, using TBI and Methotrexate to prevent GVHD [ 9 – 11 ]. Santos studied conditioning and GVHD in a rat model, and contributed to the development of a conditioning regimen with busulfan (BU) and cyclophosphamide (CY) [ 12 ]. Today, the work of these pioneers is still the basis for gold standard BMT protocols for patients with hematological diseases [ 5 , 13 ].

The birth of EBMT: ski, sun and work

In 1974, EBMT was established through the initiative of a handful of European physicians who decided to meet informally, in a small hotel in St Moritz (CH), to openly share their experiences in the burgeoning field of BMT. Together, they reviewed their cases and charts, one by one, exchanging insights on challenges and prospects. They also spent time together on the slopes of the Alps, fostering the development of a collaborative atmosphere and laying the foundations of professional bonds and friendly rivalry. Thus, EBMT was conceived, a testament to the strength of open, collaborative effort and camaraderie.

The founding members were Jon Van Rood (Leiden), who was one of the discoverers of the role of HLA in transplantation, Bruno Speck (Basel), the first to use ATG for the treatment of aplastic anemia, and Eliane Gluckman (Paris), who established the first bone marrow transplant unit in 1973 in France, after one year of training with Don Thomas in Seattle. At the time of the group’s first informal gathering in St. Moritz, the database comprised 13 patients of which 4 had been transplanted that same year. Five years later a total of 285 hematopoietic cell transplantations (HCT) had been performed and by 1989 that number had increased to 4025.

A key achievement of this founding group was recognizing that progress in BMT depended on mutual trust and collaboration. The founding members decided to name the group “the European Cooperative Group for Bone Marrow Transplantation” and to schedule annual meetings in a ski resort of the Swiss or the French Alps to facilitate open exchange of results, protocols and new ideas. After the first meeting, held in a hotel bar with 6 attendees, more and more European teams began to join, and subgroups were gradually formed. Within 5 years, the number of participants had increased from 6 to 70, reflecting increasing interest and involvement at the pan-European level. The group’s performance on skis also improved over time, although there were still some spectacular falls, fortunately without major injury. These initial gatherings nurtured scientific collaborations, lifelong friendships, and memorable moments of camaraderie and laughter.

In August 1979, on the occasion of the annual meeting of the International Society for Experimental Hematology in Rotterdam, it was decided to create the “European Foundation for Bone Marrow Transplantation”. Four working parties with chairpersons, secretaries and members were established within the Foundation, namely on aplastic anemia, acute leukemia, inborn errors and transplantation immunology.

The first meeting of the European Foundation was held at Sils Maria (Engadin), Switzerland on April 13–16, 1980 [ 14 ]. It was chaired by Bruno Speck. Over 100 scientists from all over Europe attended the meeting and 70 scientific papers were presented. EBMT was a growing organization, enthusiastically ready to engage in a collaborative effort to improve BMT outcomes.

Growth and international collaboration 1980–2000

Improving results

EBMT played a pivotal role in coordinating and standardizing transplant procedures in Europe. The group’s members agreed to analyze the practice of BMT with the aim of defining recommendations for patient and donor selection, conditioning regimens, prevention and treatment of GVHD and infection. During the 1970s, it was only possible to identify an HLA identical sibling donor for 25% of the patients under the age of 35 who needed a BMT. Among these patients, 50% experienced acute GVHD and a further 20% suffered from chronic GVHD, with a transplant related mortality rate of approximately 30–50%. Clearly, new approaches were needed to decrease the toxicity of BMT, improve outcomes and make it accessible to more patients.

The introduction of reduced-intensity conditioning compared to myeloablative conditioning with either CY-TBI or CY-BU made it possible to decrease transplant-related toxicity, especially in older populations [ 15 , 16 ]. Additionally, as cyclosporine-A progressively replaced methotrexate post-transplant, the incidence and severity of GVHD decreased [ 17 , 18 ]. Furthermore, transplant related mortality decreased through improved supportive care, the use of new antiviral agents such as acyclovir and ganciclovir against Herpes virus infection [ 19 ] and the introduction of new anti-fungal agents such as Amphotericin B and Ketoconazole.

Towards improved access to bone marrow transplant

Bone marrow donor registries

Bone marrow registries were founded to meet the challenge of finding an appropriate donor for all patients.

In 1974, the Anthony Nolan bone marrow registry (London) was established under the direction of John Goldman. with the aim of increasing the number of adult donors available for unrelated HCT. In 1988, the American National Marrow Donor Program (NMDP) was established. It involved 50 blood banks and 20 marrow transplant centers throughout the United States. In 1986, Jean Dausset and Jean Bernard founded France Greffe de Moelle, a volunteer bone marrow registry established to facilitate hematopoietic stem cell donations for patients in need of a donor. The World Marrow Donor Association (WMDA) was initiated informally in 1988 by 3 pioneers in the field of transplantation: John Goldman (UK), E Donnall Thomas (US) and Jon J. van Rood (The Netherlands). Formally established in 1994, WMDA has now become a global society of registries, cord blood banks, donor centers, collection centers, HLA-experts, regulators, researchers, technologists, and industry partners. These stakeholders work together towards a shared vision of a world where access to life-saving cellular therapies for all patients is assured and the rights and safety of donors are protected. The WMDA global data base currently lists over 41 million adult donors and cord blood units. It works closely with donor registries worldwide and has implemented a global network for the search of a suitable donor for all patients in need.

Towards HLA mismatched transplants

The analysis of unrelated donor transplants demonstrated that HLA identity for HLA-A-B-C and -DRB1 is an important factor for patient survival. This led to the recommendation to select 8/8 allele matched donors at these loci. However, while patients of Caucasian origin had an 80% chance to find a donor in the registries, the probability was lower for patients belonging to other ethnic groups [ 20 , 21 ].

After the first cord blood transplant performed in 1988 [ 22 ], unrelated cord blood banks were founded to provide alternative sources of hematopoietic stem cells for transplantation and increase the pool of mismatched donors.

The number of cord blood banks and unrelated cord blood transplants continued to increase until the year 2000 after which it began to gradually decline with the rise of related haploidentical hematopoietic stem cell transplants. (Data from WMDA).

Pioneering work on related haploidentical transplantation began in Italy, led by the group of Aversa and Martelli in Perugia. They developed the concept of utilizing a megadose of T-cell depleted peripheral blood stem cells, following a conditioning regimen with ATG and thiotepa added to CY-TBI. Promising initial results from a study published in 1994, involving 17 patients, encouraged further exploration of this approach. By 2002, the number of patients undergoing haploidentical transplantation had increased to 437 representing 7% of the total yearly number of transplants [ 23 , 24 ]. However, challenges including the cost of T-cell depletion, and delays in engraftment and immune reconstitution, hindered the widespread adoption of this technology.

Concurrently, a Chinese research group developed an alternative technique involving unmanipulated G-CSF primed bone marrow and peripheral blood cell transplantation. Patients received conditioning with ATG, followed by post-transplant immunosuppression with either rapamycin or cyclophosphamide (PTCy), yielding promising results [ 25 ]. Nevertheless, haploidentical transplantation performed using extensive ex vivo or in vivo T-cell depletion to prevent GVHD was associated with higher non relapse mortality and delayed immune reconstitution.

A significant breakthrough in the field occurred through the work of George Wesley Santos, in Baltimore, who published a study using post-transplant cyclophosphamide (PTCy) to prevent GVHD. PTCy targeted alloreactive T- cells while leaving regulatory T-cells relatively unaffected, and sparing non-dividing hematopoietic stem cells. Further refinement of this strategy by the Baltimore group involved administering PTCy after standard conditioning and post-transplant immune suppression. This streamlined approach offered the advantage of simplicity as it avoided the need for cell manipulation [ 26 – 28 ]. As a result of these advancements, there was a surge in the number of haploidentical related transplants, which have now become the preferred cell source for HLA mismatched transplants, as well a wide use of PTCY as backbone for the GVHD prophylaxis in different donor setting.

Development of the EBMT registry

Data collection based on the EBMT activity survey was introduced in 1990. It nourished the article entitled “Current trends in Hematopoietic stem cell transplant in Europe” published by Grathwohl and al in 2002. From 1990 to 2000, 44,165 allogeneic and 88,798 autologous transplants were reported, with a rapid increase across all disease categories. In 2000, 62% of the reported transplant recipients received cells from an HLA identical sibling, 7% from another related donor and 31% from a matched unrelated donor. The stem cell source changed from almost exclusively bone marrow to more peripheral blood stem cells, especially in autologous transplants [ 29 – 32 ].

The cumulative numbers of autologous and allogeneic HCT per year has been increasing with time (Fig. 1 ). Indications of transplants have been changed overtime, a recent survey shows that the major indication for allogeneic transplant is myeloid malignancies which represent 59% of the cases in contrast autologous transplant was mostly indicated in lymphoid malignancies representing 90% of the cases (Fig. 2 ) .

Concomitantly to the increase of number of patients transplanted, results have improved overtime. In AML overall survival improve mostly because of the reduction of non relapse mortality especially in older patients (Figs. 3 and 4 ). In ALL progress has been accomplished mostly by improvement of non relapse mortality and diminution of the number of relapses (Fig. 5 ).

Education and training

The EBMT has organized annual meetings at various European venues since 1980. The last meeting held in a ski resort was in Davos in 1995. Since then, the congress has been hosted in large cities capable of accommodating an ever-growing number of participants.

Between 1996 and 2016, EBMT organized 21 international Training Courses on Blood and Marrow Transplantation in partnership with the European School of Haematology (ESH). The objective of these meetings was to respond to an unmet educational need by providing the professional actors of the multidisciplinary hematopoietic stem cell transplant community with opportunities for high-level continuing training, international networking and face-to-face scientific interaction with global experts in the field.

Between 1998 and 2012, the publication of five successive editions of the ESH-EBMT Handbook on Haemopoietic Stem Cell Transplantation also attracted attention. In total, 150,000 handbooks were made available, upon request, to university libraries and individual members of the transplant community worldwide, free of charge.

The Handbook’s success also nourished the Training Course. Initially designed for a very small group of participants, the meeting grew over time until it welcomed an international audience of 180–200 attendees each year, speakers and registered participants included. To maintain an atmosphere conducive to informal scientific interaction, all speakers were requested to remain available on-site for at least two full days, and further to the plenary lectures, case study sessions and poster sessions. The design of the scientific program was adjusted to include small, informally interactive Breakfast and Dinner Table Meet the Expert sessions.

Thanks to the longstanding support of various European Commission programs and corporate partners, the organizers were able to develop a strong scholarship program and to further facilitate attendance by alternating venues across Europe. Each year, a few hours were also reserved on one afternoon of the event to give the speakers and participants the opportunity to explore the host city’s sites together.

The first ESH-EBMT Training Course was held at the Château de Montvillargenne, Chantilly, near Paris, in 1996 and many of its participants still recall how much they enjoyed the event. In the interval between the inaugural and the last event, many Training Course attendees became active members of the EBMT. Some went on to found and develop new BMT centers in their home countries, and some became international leaders in the field, returning to the Training Course as faculty members.

Toward the future: 2000 and beyond

It is April 2024 and EBMT celebrates its 50th anniversary. Today, EBMT is a modern society that has been able to strengthen its internal structure to meet the different challenges that exist today in the transplantation and other cell therapy strategies field. We stand by our mission: EBMT’s primary goal is to improve the lives of patients with blood-related disorders through research, education and advocacy. To further achieve this goal, EBMT officially embraced the concept of equality, diversity and inclusion (EDI) with the aim of becoming a more diverse and inclusive society. We believe that improving good practice in these areas is key to unlocking the potential contributions to our work of all our members and staff and, most important, critical to our wider work challenging health inequalities in patient care. In this sense, an additional step was undertaken with the creation of the Patient Advocacy Committee that was born to inform and provide a patient-oriented viewpoint to be incorporated in all related activities developed at EBMT, including its strategy and decision-making at Board level. The EBMT has nowadays more than 7000 members in over 70 countries. Patient Associations involved in the field of transplantation, gene therapy and cellular therapy related to any kind of hematopoietic stem cells or immunomodulatory cells that are interested in the activities of the EBMT can also become Centre Members.

Education

The Annual Meeting remains the most important educational event of EBMT. After three years of virtual meetings due to the impact of the COVID19 pandemic, the new normal was crystallized at the Annual Meeting in Paris with almost 5000 participants in person; we were able to enjoy not only the scientific program but also the face-to-face discussions and networking during the breaks. EBMT’s educational portfolio has increased significantly with the development of mid-size events (the International Transplant and Cellular Therapy Course in Barcelona is the most consolidated example as well as the joint meetings of different working parties) and the educational courses that most of the working parties prepare on an annual basis. The development of the Trainee Committee in 2019 and the integration of our future “transplanters” in all educational activities is another example of our interest as a society to offer a competitive educational program adapted to the needs of future generations. The COVID19 pandemic has allowed us to crystallize an online educational platform that, on the one hand, allowed us to maintain the educational project in the toughest stages of the pandemic, but which, now that the pandemic is over, has made all this educational material accessible to a wider and more diverse public. EBMT is leading educational activities with other transplant societies e.g. American Society of Transplantation and Cellular therapy (ASTCT) and with European Hematology Association (EHA) with the implementation of the EU CART Cell Course which is the biggest of its kind in Europe. Finally, the last edition of the EBMT Handbook is available in an open-access digital PDF since 14 April 2024.

Science and clinical practice

From the scientific point of view, it is important to highlight the integration of hematopoietic stem cell transplantation in the era of new drugs. The indications for transplantation have undergone significant modifications with the arrival of the new drugs (Fig. 2 ). In some cases, the number has decreased; in others, their position in the patient’s “therapeutic life” has been modified. Chronic myeloid leukemia was for many years the primary indication for allogeneic transplantation; the introduction of imatinib (STI571) as first-line treatment and, subsequently, of second- and third-generation inhibitors, has transformed this indication into a residual indication [ 33 ]. Allogeneic stem cell transplantation in chronic lymphocytic leukemia has faced a similar situation with the advent of bruton tirosinkinase inhibitors [ 34 ]. At the present time, after many years of continuous growth, increase in application of HCT seems to have slowed down [ 35 ]. The significant increase in the number of patients treated with other cell therapy strategies, basically CART cells, has contributed to this situation. The authorization by the European Medical Agency (EMA) in 2019 of three autologous CD19 constructs (axicabtagen ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) for the treatment of adult patients with aggressive B lymphomas (primarily diffuse large B-cell lymphoma) who have failed a minimum of two prior lines of therapy as well as tisagenlecleucel for the treatment of children and young people up to 25 years of age with relapsed or refractory acute B-lymphoblastic leukemia, followed by additional authorizations in other pathologies (follicular lymphoma, mantle cell lymphoma, multiple myeloma) have represented a veritable tsunami in this field and have modified the practice of HCT with its consequent decrease in number and positioning, mainly in the case of aggressive B lymphomas. A new era of hemoglobinopathies treatment began 40 years ago when allogeneic hematopoietic stem cell transplantation provided the first cure for these genetic conditions. Over 10,000 patients have received transplants since then and currently, gene therapy is at the beginning of a new era; gene therapy gives hope of providing more targeted and effective treatments, especially for individuals with rare diseases such as B-thalassemia and sickle cell disease; the Hemoglobinopathies Working Party was approved by the General Assembly in 2022 with the objective to have EBMT at the forefront of these new therapeutic challenges and opportunities for the patients. Finally, and also in the field of cell therapy, we are moving towards precision and personalized medicine based on better identification of prognostic factors both before and after the procedure and which allows us to make better use of new drugs (targeted therapy) in those patients who need them. Last but not least, we must highlight the great advances in the prevention and treatment of complications derived from allogeneic transplantation (infectious complications, acute and chronic graft-versus-host disease), which have undoubtedly led to a significant decrease in procedure-related mortality and improved the quality of life of our patients.

The upgrade of the registry

In August 2023, EBMT was thrilled to announce the official launch of the new registry platform, a remarkable achievement reflecting years of dedicated teamwork. This innovative platform replaced ProMISe and Castor, streamlining our data management practices for a more cohesive user experience. The purpose of the EBMT Registry remains clear: to provide a pool of data to EBMT members to perform studies, assess epidemiological trends, and ultimately improve patients’ lives. Nowadays, the EBMT Registry holds data on over 700,000 patients that have undergone HCT and over 7000 patients being treated with CART cells In 2019, EBMT received a regulatory qualification from the European Medicine Agency (EMA) on the use of its patient registry to support novel CAR T-cell therapies. Currently several Post Authorisation Safety studies based on secondary use of their registry data are ongoing at the EBMT.

Accreditation and benchmarking strategies

EBMT has always been committed to accreditation and JACIE develops and maintain global standards for the provision of quality medical and laboratory practice in cellular therapy. Based on these standards, JACIE offers accreditation to transplant programs in order to encourage health institutions and facilities to establish and maintain quality management systems. The activity of JACIE significantly suffered from COVID19 pandemia but it has returned back in “our new normality”; JACIE received 97 applications in 2023 which is approximately 30% increase in comparison to 2022. The number of inspections carried out increased to 77, which is the second highest number of inspections in JACIE history (2019: 78 inspections). This shows that JACIE has firmly returned to pre-pandemic. The number of centers accredited was 68 in comparison to 15 in 2022 and 27 in 2021.

In 2016, the EBMT Board and the JACIE Committee launched a benchmarking project directed at EBMT transplant Centers. Benchmarking provides transplant professionals with a means to assess how their unit is performing compared to the wider BMT community. In addition, it can reassure patients and payers with respect to the clinical performance and cost-effectiveness of their clinical BMT teams and services. Regulators see that benchmarking is an additional component to ensuring safe care of patients. This strategic and very successful project was extremely well led by Riccardo Saccardi that sadly passed away this last February.

GoCART

The field of cell and gene therapy is one of the most exciting developments in medicine. The EBMT and the EHA announced a strategic partnership to empower Europe to become a global leader in the cellular therapy field for hematological diseases. EBMT and EHA joined forces and brought their collective resources and expertise to the newly founded GoCART Coallition, a multi-stakeholder coalition of patient representatives, health care professionals, pharmaceutical companies, regulators, Health Technology Assessment (HTA) bodies and reimbursement agencies, and medical organisations, collaborating to maximise the potential of cellular therapies manufactured from cells and tissues of hematopoietic origin.

Happy 50th Anniversary EBMT! Jon Van Rood, Bruno Speck and Eliane Gluckman did a great job in 1974! That small group of hematologists whose interests fluctuated between the scientific discussion of patients, the development of friendships and the improvement of alpine skiing practices has become a scientific society that aims to be the umbrella for all professionals involved in the world of hematopoietic stem cell transplantation and cell therapy and all related activities with a single common goal: to improve the long-term survival of patients with oncohematological diseases who are candidates for this type of treatment.

Author contributions

EG and AS wrote the manuscript, participated in edits, reviewed the draft and approved the final version.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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