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Editorials
resents the second important pillar in the development of References
optimized transplantation protocols. Specifically, the use of antihuman T lymphocyte globulin (ATG), a polyvalent preparation generated in rabbits against Jurkat T cells, was introduced several decades ago. Antithymocyte gobulin, derived from rabbits or horses against human thymocytes, has predominantly been used for the treatment of severe aplastic anemia but also within conditioning for allogeneic HCT in selected protocols, mainly for non-malignant indi- cations.8 The pivotal trial testing ATG in the setting of unre- lated donors and intensive conditioning suggested a signifi- cant reduction in the incidence of chronic graft-versus-host disease without an increase in the risk of relapse.9 While this trial tested a dose of 60 mg/kg ATG (day -3 to -1), a sim- ilar finding was made after allogeneic HCT from matched siblings applying 30 mg/kg again within intensive condi- tioning.10 Both trials included patients with acute leukemia and myelodysplastic syndromes. As a note of caution, a second controlled trial performed in the unrelated donor setting did not confirm the initial observations, suggesting a potential interaction between the choice of conditioning regimen and the chosen ATG regimen.11 So far, no random- ized trial had formally tested ATG after reduced intensity conditioning in transplants for a specific indication. Robin and coworkers now present the results of a retrospective analysis performed in patients with myelofibrosis receiving reduced intensity conditioning.12 Interestingly, ATG reduced the cumulative incidence of acute graft-versus-host disease while it did not affect the rate of chronic graft-ver- sus-host disease. Although the authors speculate that this may be due to the use of reduced intensity conditioning, there might be various other factors that could lead to dif- ferential effects in this specific group of patients, most of whom still have relatively high lymphocyte counts and organomegaly which can influence the pharmacodynamics of ATG.13
Although both trials address different aspects in the effort to optimize outcomes after allogeneic HCT, they clearly demonstrate that patient and disease characteristics but also graft source and choice of donor can significantly affect the outcome of treatment. Integrating the mentioned factors, the current toolbox offers conditioning protocols of almost all intensities including sequential regimens14 as well as var- ious options of modulating allogeneic immune responses such as by graft manipulation or in vivo T-cell depletion. Taking advantage of all available knowledge gained by arti- ficial intelligence and large databases15 may enable design of the ideal preparative regimen and post-grafting immuno- suppression for a given patient and in a specific immuno- genetic setting thereby making allogeneic HCT a tailored approach comparable to that of several other current strate- gies in modern oncology (Figure 1).
1. GiraltS,EsteyE,AlbitarM,etal.Engraftmentofallogeneichematopoi- etic progenitor cells with purine analog-containing chemotherapy: har- nessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89(12):4531–4536.
2. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91(3):756–763.
3. McSweeneyPA,NiederwieserD,ShizuruJA,etal.Hematopoieticcell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390–3400.
4. Sorror ML, Sandmaier BM, Storer BE, et al. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA. 2011;306(17):1874–1883.
5. Bornhauser M, Kienast J, Trenschel R, et al. Reduced-intensity condi- tioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13(10):1035–1044.
6. Monaco F, Scott BL, Chauncey TR, et al. Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms. Haematologica. 2019;104(6):1221-1229
7. Adkins DR, DiPersio JF. Total body irradiation before an allogeneic stem cell transplantation: is there a magic dose? Curr Opin Hematol. 2008;15(6):555–560.
8. Bacigalupo A. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant. 2005;35(3):225–231.
9. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host dis- ease prophylaxis with or without anti-T-cell globulin in haematopoiet- ic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855– 864.
10. Kröger N, Solano C, Wolschke C, et al. Antilymphocyte Globulin for Prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374(1):43–53.
11. SoifferRJ,KimHT,McGuirkJ,etal.Prospective,randomized,double- blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35(36):4003–4011.
12. Robin M, Chevret S, Koster L, et al. Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis. Haematologica. 2019;104(6):1230-1236.
13. Kennedy VE, Chen H, Savani BN, et al. Optimizing antithymocyte globulin dosing for unrelated donor allogeneic hematopoietic cell trans- plantation based on recipient absolute lymphocyte count. Biol Blood Marrow Transplant. 2018;24(1):150–155.
14. Schmid, C, Schleuning, M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108(3):1092–1099.
15. Shouval R, Bondi O, Mishan H, Shimoni A, Unger R, Nagler A. Application of machine learning algorithms for clinical predictive mod- eling: a data-mining approach in SCT. Bone Marrow Transplant. 2014;49(3):332–337.
haematologica | 2019; 104(6)