Insight

The European Society for Blood and Bone Marrow Transplantation celebrates 60 years of haematopoietic stem cell transplantation – highlights of the 43rd EBMT Annual Meeting
Katrina Mountfort, Touch Medical Media, Reading, UK

This year marks the 60th anniversary of one of the most important developments in medicine. In September 1957, a landmark publication by Thomas et al. entitled, ‘Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy’ was published in the New England Journal of Medicine.1 The first successful long-term survivors of haematopoietic stem cell transplantation (HSCT) were reported at the end of the 1960s. During the 1970s, HSCT was used for leukaemia only after failure of all other treatment, and the survival rate was poor. In the 1980s, outcomes improved greatly thanks to improved control of infections, the use of peripheral blood as the source of stem cells, and the ability to select donors who were not family members.2 Since then, numerous advances have occurred in the field of HSCT, and the technique has evolved to encompass a diverse range of cellular and gene therapies. Such innovations formed the focus of the 43rd European Society for Blood and Bone Marrow Transplantation (EBMT) Annual Meeting, which was held in Marseille, France between 26-29 March 2017.

A key theme of this year’s meeting was the role of double autologous stem cell transplantation (ASCT), in which two successive ACSTs are performed, with the aim of prolonging the duration of response. This approach emerged around 15 years ago and has recently been rejuvenated, particularly for patients with high-risk cytogenetics. A recent phase III study confirmed its benefits over single ASCT in multiple myeloma (MM) patients with disease-related factors predicting for poor prognosis.3

Deep minimal residual disease (MRD) negativity is another of this year’s hot topics. The development of techniques with sufficient sensitivity to detect subclinical levels of disease, such as flow cytometry or polymerase chain reaction, represents another milestone in the treatment of haematological malignancies. A growing body of evidence shows that detection of MRD provides strong prognostic information, and MRD status can be categorised to define deep response. Current therapies are producing unprecedented depths of response, and next generation flow and sequencing methods to measure MRD in bone marrow have sensitivities in the range of 10-5‒10-6 cells.4 A recent meta-analysis concluded that MRD negativity following treatment for newly diagnosed MM is associated with long-term survival.5 This adds to a growing body of evidence suggesting that assessment for MRD should be included as a surrogate endpoint for clinical studies aiming to obtain accelerated approval for new myeloma drugs.4

Novel therapies are key feature of any conference, and this year’s meeting featured sessions on monoclonal antibodies such as blinatumomab, a CD19 bi-specific anti-CD19/CD3 antibody and inotuzumab, a CD22 monoclonal antibody for the treatment of acute lymphoblastic leukaemia (ALL). Although most of these agents are currently being evaluated in the refractory/relapsed ALL treatment setting,6 the most active agents may become incorporated into the first-line treatment regimens, which may induce higher rates of MRD negativity, reduce the need for intensive and prolonged chemotherapy regimens, and significantly increase the cure rates in adult ALL.7 Thanks to the advent of these novel therapies, the natural history of ALL is being modified.

Novel induction regiments for MM were also presented. The standard induction treatment regimens for patients with MM who are eligible for ASCT involve triplet regimens using an immunomodulator, such as thalidomide or lenalidomide, or a proteasome inhibitor, such as bortezomib. Previous attempts to improve outcomes using four-drug regimens that contain both bortezomib and lenalidomide have been associated with excessive toxicity. The replacement of bortezomib with second-generation agents such as carfilzomib, reduces toxicity and has driven further research into novel induction regimens.8

The value of supportive care was also discussed at the meeting. In patients undergoing HSCT, fungal infections such as invasive pulmonary aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. Novel antifungal agents include include isavuconazole, voriconazole plus an echinocandin (combination therapy), caspofungin liposomal amphotericin B, and other lipid formulations of amphotericin B.9 Cytomegalovirus (CMV) management has been one of the major challenges in the history of HSCT. In the 1970s and 80s, one in five patients undergoing HCST died due to CMV disease, largely CMV pneumonitis. Today, the figure is less than 2%.10 Recent advances in the development of new antivirals, adoptive immunotherapy and DNA-CMV vaccines should reduce this figure even further in the near future.11

In conclusion, the field of stem cell transplantation has expanded vastly in the last 60 years, and progress continues to accelerate. Experts are agreed that the field has also become more complex and the focus is now on improving individual patient outcomes through combinations of novel therapeutic agents and transplantation.

References
1. Thomas ED, Lochte HL Jr., Lu WC, et al., Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, N Engl J Med, 1957;257:491-6.
2. Thomas ED, Landmarks in the development of hematopoietic cell transplantation, World J Surg, 2000;24:815-8.
3. Cavo M, Petrucci MT, Di Raimondo F, et al., 991 Upfront Single Versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial), Presented at the ASH 58th Annual Meeting and Exposition, December 3-6, 2016, San Diego, CA.
4. Anderson KC, Auclair D, Kelloff GJ, et al., The role of minimal residual disease testing in myeloma treatment selection and drug development: current value and future applications, Clin Cancer Res, 2017, epub ahead of print.
5. Munshi NC, Avet-Loiseau H, Rawstron AC, et al., Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis, JAMA Oncol, 2017;3:28-35.
6. Kantarjian H, Stein A, Gokbuget N, et al., Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia, N Engl J Med, 2017;376:836-47.
7. Jabbour E, Kantarjian H, Immunotherapy in adult acute lymphoblastic leukemia: the role of monoclonal antibodies, Blood Advances, 2016;2:260-4.
8. Muchtar E, Gertz MA, Magen H, A practical review on carfilzomib in multiple myeloma, Eur J Haematol, 2016;96:564-77.
9. Gedik H, Simsek F, Yildirmak T, et al., Novel antifungal drugs against fungal pathogens: do they provide promising results for treatment?, Indian J Hematol Blood Transfus, 2015;31:196-205.
10. Gooley TA, Chien JW, Pergam SA, et al., Reduced mortality after allogeneic hematopoietic-cell transplantation, N Engl J Med, 2010;363:2091-101.
11. de la Camara R, CMV in hematopoietic stem cell transplantation, Mediterr J Hematol Infect Dis, 2016;8:e2016031.