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Editorials
Figure 1. Summary of key results from Koreth et al.3 (JCO 2012) and from the current study.1 Results are shown for Arm A (tacrolimus and methotrexate), Arm B (bortezomib added to tacrolimus and methotrexate) and Arm C (bortezomib and tacrolimus with sirolimus substituted for methotrexate), as compared to tacrolimus and methotrexate used in the JCO 2012 study.3 Diamonds indicate the incidence frequencies of grades II – IV GvHD and III – IV GvHD, and bars indicate the 95% confidence intervals. All patients in the JCO 2012 study had HLA-mismatched unrelated donors. In Arms A, B and C of the current study, all patients had HLA-A, B, C, DRB1–matched unrelated donors. Data in the figure exclude GvHD that occurred after relapse of the pretransplant disease. Results for grade III – IV GvHD are shown on a log scale in order to visualize the lower limits of the 95% confidence intervals more clearly. GvHD: graft-versus-host disease; CI: confidence interval.
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dence frequencies of grade II – IV GvHD were 31% in control patients treated with tacrolimus and methotrex- ate, and 26% in patients treated with bortezomib added to tacrolimus and methotrexate.6
Arm C of the current study1 tested a regimen of borte- zomib and tacrolimus with the substitution of sirolimus for methotrexate when compared to Arm B. This substi- tution was motivated by a desire to enhance the survival and function of T-regulatory cells, thereby possibly facili- tating the development of tolerance. The 15% incidence of grade II – IV GvHD in this group appears to be encour- aging when compared against the 33% incidence in Arm A. More importantly, however, the results for grade III – IV GvHD were somewhat higher in Arms B and C than in Arm A. Here, the 9% incidence in Arm B and the 11% incidence in Arm C appear to be consistent with the ~10% incidence of grade III – IV GvHD observed with other current approaches, while the 2% incidence in Arm A appears to be much better than expected. In the BMT CTN 1203 PROGRESS study, for example, the cumula- tive incidence frequencies of grades III – IV GvHD were 13% in the controls treated with tacrolimus and methotrexate, and 8% in patients treated with borte- zomib added to tacrolimus and methotrexate.6
The current results raise the question of whether data from the phase I/II trial truly justified the effort to inves- tigate bortezomib-based immunosuppression in the sub- sequent three-arm trial and the BMT CTN 1203 PROGRESS trial. Enthusiasm for these studies was based primarily on a comparison of outcomes between patients enrolled in the phase I/II study and a group of 176 patients who received tacrolimus and sirolimus for immunosuppression after HLA-matched unrelated trans- plantation.3 In this comparison, the 22% incidence of grade II – IV GvHD in the phase I/II study did not differ statistically from the 11% incidence in the 176 patients with HLA-matched unrelated donors. The absence of sta- tistical significance therein, however, cannot be interpret- ed as indicating that the incidence rates are similar. P-val-
ues >0.05 indicate only that the results were not demon- strably different between the two groups, given their respective sizes. In this case, the comparison actually showed a two-fold difference in the incidence of grade II – IV acute GvHD.
A further question is whether grade II – IV GvHD actu- ally represents the most appropriate primary endpoint in studies evaluating immunosuppressive regimens after allo- geneic HCT. Results of a recent CIBMTR study showed that grade II acute GvHD has no statistically significant association with the risk of treatment failure defined as death or relapse, whereas grades III and IV acute GvHD were associated with increased risks of treatment failure.7 These observations suggest that clinical trials should focus on preventing grade III – IV acute GvHD, as opposed to grade II – IV acute GvHD. The prior report by Koreth et al.3 did not compare the incidence rates of grade III – IV acute GvHD between patients enrolled in the phase I/II study and the 176 patients who received tacrolimus and sirolimus for immunosuppression after HLA-matched unrelated transplantation.
To some extent, we have become victims of our own success in our efforts to prevent grade III – IV acute GvHD. A 1:1 randomized trial would require approxi- mately 200 patients per arm to test the difference between a 10% incidence and a 3% incidence at 80% power and a 0.05 two-side type-1 error. A larger effect size would require fewer patients. As an alternative, sur- vival to 1 year without prior grade III – IV acute GvHD, chronic GvHD requiring systemic treatment, or relapse has become a very popular compound endpoint for acute GvHD prevention studies.7 Current typical estimates for this GvHD-free/relapse-free survival (GRFS) endpoint are in the 35% range, which leaves considerable room for improvement.7 However, grade III – IV acute GvHD makes the smallest contribution among the four compo- nents of this compound endpoint. Moreover, the risks of non-relapse mortality and relapse are heavily influenced by factors that are not associated with the risk of grade III
haematologica | 2018; 103(3)