Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia
Peffault de Latour R, et al
The New England Journal of Medicine 2022;386:11-23.
In recent years, it has been challenging for EBMT to conduct its own investigator-led clinical trials across international boundaries, but the Severe Aplastic Anaemia Working Party has delivered impressively with the completion and full publication of the primary paper of this landmark trial - albeit with a ‘non-transplant’ trial. This magnificent effort is now robustly changing the paradigm and guidelines for treatment of severe aplastic anaemia, enhancing patient experience, and potentially sparing some patients of having to undergo the additional toxicities of an early allogeneic transplant.
For some time, early phase data has supported eltrombopag, an oral thrombopoietin-receptor agonist, might augment the standard immunosuppressive therapy of horse-antithymocyte globulin (ATG) and cyclosporine, but there was uncertainty and concerns about safety and efficacy. Between 2015-2019, the open label RACE trial (=Randomized, Multicenter Trial Comparing Horse ATG plus Cyclosporine with or without Eltrombopag as First-Line) recruited patients with severe aplastic anaemia or very severe aplastic anaemia aged 15 years or older and assigned 96 patents to oral eltrombopag 150 mg per day from day 14 combined with standard horse-ATG (using ‘ATGAM’) and cyclosporine versus 101 patients in the control arm treated with standard horse-ATG (‘ATGAM’) and cyclosporine alone. The primary endpoint was haematological complete response at 3 months (defined as Hb>10 g/dL, neutrophil count >1.0 x109/L, platelets >100 x109/L in patients who had not received transfusions). Patients maintained eltrombopag for up to 6 months unless they achieved a complete response at 3 months. Complete response at 3 months was significantly better in the eltrombopag arm i.e. 22% versus 10%, and at six months overall response (complete + partial) were 68% versus 41%, with median times to first response of 3 months versus 8.8 months respectively. Safety aspects, including evaluation of karyotypic abnormalities and somatic mutations using a 31-gene targetted molecular bar coded panel, were similar in both groups. Two year overall survival was similar (85 versus 92%) and cumulative incidence of relapse was similiar in both groups. Twenty-three (11 versus 12) patients underwent HSCT.
This landmark study has cemented eltrombopag in combination with horse-ATG (‘ATGAM’) and cyclosporine as a new standard of care in newly diagnosed patients with severe and very severe aplastic anaemia, and provided reassurance of the safety particularly in relation to clonal evolution. Further generations of outputs from this study, including translational and long-term follow up studies, will be valuable for our understanding of the disease process and best clinical practice.
Read our previous news: "EBMT trial demonstrates improvements in immunosuppressive treatment of patients with Severe Aplastic Anemia"
Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.
Greenfield DM, et al
Bone Marrow Transplant. 2021 Nov;56:2820-2825.
Have you often wondered whether some patients who beat their underlying diagnosis with HSCT appear to have problems with weight gain, hypertension, diabetes and other cardiovascular risk factors in the long-term follow up clinic? Some patients even get ischaemic heart disease or stroke. Obviously ageing plays a role, but metabolic syndrome (a constellation of cardiovascular risk factors) is well recognised in long term cancer survivors, but perhaps less well characterised in HSCT survivors. The causes are multifactorial, but include pathophysiological impacts of drugs and radiotherapy (in both conditioning and pre-transplant treatments), endothelial damage, endocrine, and GVHD and its treatments (including steroids and Ciclosporin), along with psychosocial and behavioural factors.
Under the Transplant Complications Working Party, this cross-sectional, multi-centre, non-interventional study of 453 adult HSCT patients surviving a minimum of 2 years post-transplant has shown an overall prevalence of metabolic syndrome to be 37.5%, which rises to 53% in patients over 50 years. Interestingly autologous and allogeneic HSCT patients are similarly affected, with no association with graft-versus-host disease or current immunosuppressant therapy. Perhaps not surprisingly, metabolic syndrome was age-related and associated with a higher rate (26.7%) of cardiovascular events (i.e. coronary heart disease, cerebrovascular accident, peripheral vascular disease) compared with those without metabolic syndrome (9%). This study makes a good case for routine screening for metabolic syndrome according to harmonised definitions, and proactive management integrated into long-term follow-up care following both allogeneic and autologous HSCT. Future research is needed in this area, especially mechanistic studies of cardiovascular damage risk following HSCT and prospective interventional trials.
Risk of infectious complications in adult patients after allogeneic hematopoietic stem cell transplantation depending on the site of central venous catheter insertion-multicenter prospective observational study, from the IDWP EBMT and Nurses Group of EBMT
Snarski E, et al
Bone Marrow Transplant. 2021;56:2929-2933.
Practical considerations relating to venous access is a daily necessity in our clinical practice, not just in relation to risks at the time of insertion, but also there are major implications for patients particularly in relation to infectious complications, which frequently complicate the peri-transplant period and downstream may be a cause of recurrent readmission, all of which add to healtcare costs. In a multicentre, prospective non-interventional observational study involving 11 centres across 8 countries, the IDWP and Nurses Group have re-visited this important (and arguably neglected) area in terms of a very specific question for adult allogeneic transplant patients; should lines be inserted in the subclavian vein (SCV) or in the inferior jugular vein (IJV)? They looked at 232 consecutive patients (86 with IJV and 146 SVC insertions) for CVC or bloodstream related infections in a centre independent manner. Better outcomes (i.e. less infections, using ECDC criteria) were observed with SCV insertions (13% with SVC versus 23% with IJV insertions). In addition, central line-associated bloodstream infection per 1000 patient days showed significantly less rates in SJV (2.79) versus IJV (7.93). Non-infectious complications were similar in both arms. The potential reasons for these benefits are discussed.
Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.
Phelan R, et al
Transplant Cell Ther. 2021 Oct 29:S2666-6367(21)01329-4.
This collaborative project, involving transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals brought together by the Late Effects and Quality of Life Working Committee of CIBMTR, and the Transplant Complications Working Party of EBMT, to undertake a thorough systematic review of published literature relating to adult male-specific late effects in HSCT. Areas covered include genital chronic graft-versus-host disease (GVHD), hypogonadism, infertility, sexual dysfunction, and bone complications, as well as risks of emergent cancers – not only prostate, penile, and testicular but also potentially skin and oral mucosal malignancies. Incidence, screening, diagnosis, risk factors, treatments and quality of life aspects were all systematically reviewed. One major output was a limitation of high-quality evidence specifically for HSCT patients, which precludes strong recommendations for management of complications, other than extrapolating those applying to the general population or cancer populations, such as for management of hormone replacement therapies. Despite this limitation, practical clinical recommendations are made where possible for a range of issues. Recommendations are also made for improved data registration (e.g. in relation to genital GVHD, sexual dysfunction, fertility and conception). Further prospective research should be undertaken, including interventional trials in the male HSCT population to help define the risks and best therapeutic approaches for gender-specific late effects.
Mother donors improve outcomes after HLA haploidentical transplantation: A Study by the Cellular Therapy and Immunobiology Working Party of the EBMT
Ruggeri L, et al
Transplant Cell Ther. 2022 Jan 10:S2666-6367(22)00001-X.
Over the years a body of evidence has accumulated to support the maternal immune system being permanently affected by trans-placental passage of foetal cells during pregnancy and leading to sensitization, tolerization, and even potential clinical autoimmune diseases. Thus, if mothers were to be used as donors for their children then there may have broader immunological impacts potentially affecting outcomes.
This recent retrospective EBMT CTIWP study looked at 409 (with 307 adults) patients and provides further support for better outcomes in T-cell depleted transplant using maternal donors, where there was reduced relapse incidence and better graft-versus-host/relapse-free survival. Overall, the results provide further support for the choice of mothers as donors in haploidentical transplantation, especially T-cell depleted, for acute leukaemia and potentially other diseases.
Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT
Battipaglia G et al
Bone Marrow Transplant. 2022 Jan 25.
The post-transplant cyclophosphamide ‘PTCy’ story continues to be one of the greatest developments in modern HSCT techniques, enabling safer delivery of haploidentical transplants where no fully matched donors are available. In recent years, PTCy has been extended to other types of allogeneic transplant, in both matched donor and mismatched donor setting. This retrospective study from the ALWP explored the use of PTCy in the setting of 1-antigen mismatched versus haploidentical transplants for AML patients in complete remission. Three groups were compared; 1 antigen-mismatched unrelated donors using peripheral blood (n = 155), and haploidentical using bone marrow (n = 647) and haploidentical using peripheral blood (n = 949). Irrespective of whether peripheral blood or bone marrow was used, transplants from haploidentical donors with PTCy had a lower overall survival, leukaemia free survival, and a higher treatment related mortality compared with transplants with 1-antigen mismatched unrelated donors and PTCy. No differences were observed for overall graft-versus-host/relapse-free survival and relapse incidence, but haploidentical bone marrow transplantation was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD). There was no difference between groups for chronic GVHD. This study supports the use of with PTCy and 1-antigen-mismatched unrelated donor transplantation as a valid alternative donor source. Defining the best algorithms for clinical decision making in selection of alternative donors is an area for continuing development. Further studies, including prospective trials, of allogeneic transplantation protocols using donors of varying histocompatibility with recipients should be help to clarify the algorithms to optimise patient outcomes with PTCy.