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Editorials
– IV acute GvHD. For these reasons, the GRFS endpoint represents an unreliable surrogate for the ability of an intervention to prevent grade III – IV acute GvHD.
The current report by Koreth et al.1 represents a well- controlled attempt to evaluate the merits of bortezomib for immunosuppression after HCT with reduced intensi- ty conditioning regimens. The report is newsworthy, because the negative results do not support expectations that bortezomib-based regimens might have a major effect on the risk of grade III – IV acute GvHD, even with the substitution of sirolimus for methotrexate in Arm C. With the benefit of hindsight, one could question whether the expectations based on results of the phase I/II study were realistic.
The experience from testing bortezomib yields impor- tant lessons for planning future trials. First, grade III – IV acute GvHD should be defined as the primary endpoint in trials designed to test an intervention intended to pre- vent acute GvHD. Second, the benchmark incidence of grade III – IV acute GvHD should be set at 10 – 15%, depending on the relationship and HLA-matching between the donor and recipient. Third, early phase trials should be designed to test whether an intervention can reduce the incidence of grade III – IV acute GvHD to 2% or less, as it will not be feasible to determine whether any smaller effect size holds true in a phase III trial. Early phase and later phase trials should have rules that discon- tinue enrollment when initial results indicate that the intervention is not likely to reach this benchmark of suc- cess. Finally, although the GRFS endpoint should not be used as the primary endpoint in trials of interventions
intended to prevent grade III – IV acute GvHD, it remains important to demonstrate that successful prevention of grade III – IV acute GvHD does not come at the expense of increasing the risk of non-relapse mortality or the risk of recurrent or progressive malignancy.
References
1. Koreth J, Kim HT, Lange PB, et al. Bortezomib-based immunosup- pression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Haematologica. 2018;103(3):522-530.
2. Mohty M, Brissot E, Savani B and Gaugler B. Effects of bortezomib on the immune system: a focus on immune regulation. Biol Blood Marrow Transplant. 2014;19(10):1416-1420.
3. Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-ver- sus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol. 2012;30(26):3202-3208.
4. Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched donors. Blood. 2009;114(18):3956-3959.
5. HoV,KimH,WindawaiS,etal.HLAmismatchandclinicaloutcome after unrelated donor (URD) non-myeloablative hematopoietic stem cell transplantation (NST). Biol Blood Marrow Transplant. 2005;11(suppl 1):S14.
6. Bolaños-Meade J, Reshef R, Fraser R, et al. Novel approaches for graft-versus-host disease (GvHD) prophylaxis: Primary results of Progress I multicenter trial of matched allogeneic hematopoietic cell transplantation (alloHCT) using reduced intensity conditioning (RIC) BMT CTN 1203. Biol Blood Marrow Transplant. 2018 Epub ahead of print].
7. Pasquini MC, Logan B, Jones RJ, et al. Blood and marrow transplant clinical trials network report on development of novel endpoints and selection of promising approaches for graft-versus-host disease pre- vention trials. Biol Blood Marrow Transplant. 2018 [Epub ahead of print]..
Use of desmopressin in the treatment of hemophilia A: towards a golden jubilee
Pier Mannuccio Mannucci
Scientific Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation and University of Milan, Italy
E-mail: piermannuccio.mannucci@unimi.it doi:10.3324/haematol.2018.187567
Throughout the 1970s, the availability and safety of coagulation factors, employed for replacement therapy in patients with hemophilia (PWH), were very far from what they are nowadays. Plasma-derived concentrates of factor VIII (FVIII) and IX started to be industrially manufactured, but they were generally avail- able in limited amounts in most countries, and thus used only for the acute treatment of bleeding episodes (so called ‘on-demand regimen’), but not for the treatment of choice, i.e., the prevention of bleeds by means of regular- ly spaced infusions (prophylaxis regimen). Most impor- tantly, these products, produced from plasma pooled from thousand of donors, transmitted the hepatitis virus- es with extremely high frequency; the agent causing hep- atitis B and, more often, the so called non-A, non-B virus, which was only identified in 1989 as the hepatitis C virus. These bloodborne viruses heralded the bleak era of infection with the human immunodeficiency virus (HIV),
that started to contaminate plasma-derived coagulation factor concentrates at the end of the 1970s, eventually leading to the first appearance in PWH of the acquired immunodeficiency syndrome (AIDS) in 1982, which caused such a high toll of deaths during the 1980s and the 1990s.
With this background, it is not surprising that in the 1970s and earlier a multitude of research efforts were directed towards the development of pharmacological alternatives to blood products. These agents were felt particularly necessary in patients with mild hemophilia A who, having measurable plasma levels of FVIII of 6% of normal or more, bleed much less frequently than those with severe disease and unmeasurable FVIII levels. In general they have little risk of mortality and morbidity, and their main clinical problem is excessive bleeding after trauma or surgery whereas, at variance with severe hemophilia, spontaneous bleeding episodes and joint
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