Page 169 - Haematologica3

Bortezomib-based RIC HSCT: Phase II RCT
HLA-mismatched T-replete RIC HSCT, we undertook a prospective randomized evaluation of aGvHD prophylax- is with conventional tac/mtx (arm A) vs. two novel regi- mens of short-course bort for transplantation recipients lacking 8/8 HLA-matched related donors: bort plus tac/mtx (arm B), and bort plus sir/tac (arm C).
In our study, Bort, limited to three doses peritransplan- tation (day +1, +4 and +7), did not add toxicity. No bort doses were missed or modified. No subjects developed toxicities of prolonged/delayed bort administration (e.g., neuropathy, colonic necrosis). Comparing treatment arms, no increase in hepatic VOD, AKI or TMA/HUS was noted for bort-based regimens vs. tac/mtx.
Engraftment was rapid and sustained, with robust donor chimerism by day 30 that was sustained and com- parable across treatment arms. The addition of bort alone did not appear to impair immunologic recovery, with sim- ilar counts of T cells (CD4, CD8), B cells and NK cells in the conventional tac/mtx vs. bort/tac/mtx arms. Count recovery for arm C (bort/sir/tac) was lower, as we previ- ously documented for other sir-based cohorts.10 As hypothesized, there was relative sparing of Treg reconsti- tution with arm C (bort/sir/tac), with no impairment of Treg count recovery and elevated Treg:Tcon ratios.
The clinical impact of these systematic immunologic dif- ferences, however, remains unclear. Importantly, the 2-year NRM incidence was low (ranging from 6.4% to 16%) and did not differ significantly between treatment arms. Relapse was in the expected range after RIC HSCT (ranging from 24% to 36%), and did not differ significantly between treat- ment arms. In this study, survival, while not differing signif- icantly between treatment arms, with 2-year OS ranging from 61% to 62% (P=0.98), appeared better than anticipat- ed for 7/8 and 8/8 HLA-matched recipients, plateauing at 50% and 66%, respectively, in contrast to 1- and 3-year reg- istry benchmark survivals recently reported for 7/8 and 8/8 donor recipients, of 48%→30% and 55%→38%, respec- tively.2 We highlight a lack of significant difference between treatment arms with regard to the primary endpoint of grade II-IV aGvHD rate by day +180.
In the context of delayed T-cell reconstitution noted for arm C, this suggests that the combination of a CNI (tac) plus mTOR inhibitor (sir) provides IS without long term tolerizing effects. While it is possible that longer duration of tac/sir immunosuppression in arm C beyond day +180 may have better prevented aGvHD, ultimately, aGvHD deferral rather than long-term amelioration remains a pos- sibility. In subgroup analysis for the 8/8 HLA-matched recipients, bort-based regimens had a borderline trend towards grade II-IV aGvHD benefit vs. tac/mtx, with a cumulative incidence of 17% vs. 33%, respectively, (P=0.08). However, grade III-IV severe aGvHD rates were not improved, and for 7/8 MMD grafts a similar trend for aGvHD benefit of bort-based regimens was not apprecia- ble, though sample size was limited.
Our trial has strengths due to its appropriate size in the phase II context, and its direct prospective randomization to conventional tac/mtx vs. two novel bort-based GvHD prophylaxis regimens. Concerns regarding open-label treatment assignment are ameliorated by the minimal dropout rate and the mITT analysis to further avoid bias, while the ‘hard’ endpoints of GvHD, NRM, relapse and survival additionally obviate assessment bias concerns.
Our primary finding is that, as tested, bort-based regi- mens did not appear to provide additional benefit for grade II-IV aGvHD prevention in T-replete PBSC RIC HSCT, failing to meet the protocol-specified 25% reduc- tion in aGvHD incidence for success. Our phase II RCT requirements for success were stringent, which limits our ability to detect lower, albeit potentially clinically mean- ingful benefit with bort. However, it is also notable that conventional tac/mtx outcomes were better than antici- pated, a finding similar to that recently reported in other contemporary randomized HSCT trials.21
These data highlight the inadequacy of non-randomized comparators for evaluating early phase single arm inter- ventional studies, and document, as an updated standard, the improved MMD and MUD RIC HSCT outcomes achievable with conventional tac/mtx in this study (2-year OS of 58% and 62%, respectively). In the future, prospec- tive trials of alternative donors (e.g., UCB, haplo) and novel GvHD prophylaxis regimens (e.g., maraviroc, PTCy) may need to benchmark these outcomes. In con- trast, the bar for the novel GRFS endpoint appears far lower, ranging from 8% to 12% in our study, with no sig- nificant difference between treatment arms (P=0.53).
In summary, mature data from this open-label 1:1:1 three-arm phase II RCT indicates that the bort-based reg- imens evaluated appear to provide lower than anticipated grade II-IV aGvHD benefit compared to conventional tac/mtx in T-replete PBSC RIC HSCT. While we note the potential benefit of bort for 8/8 HLA-matched transplants, direct phase III prospective randomization is required in order to confirm such a benefit. Overall, however, the lack of benefit for other transplantation outcomes (NRM, relapse, chronic GvHD, and survival) suggests limited util- ity for bort prophylaxis in the doses and combinations assessed. Alternative proteasome inhibitor combination regimens (e.g., with PTCy) should also be considered.
Acknowledgments
We thank clinical research nurses Susan Stephenson RN and Mildred Pasek RN. JK is a Scholar in Clinical Research of the Leukemia and Lymphoma Society.
Funding
This study was supported in part by Millennium Pharmaceuticals Inc., the Jock and Bunny Adams Research and Education Endowment, and the National Institutes of Health CA183560, CA183559, and P01CA142106.
References
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2. Verneris MR, Lee SJ, Ahn KW, et al. HLA
mismatch is associated with worse out- comes after unrelated donor reduced-inten- sity conditioning hematopoietic cell trans- plantation: an analysis from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(10):1783-1789.
3. Nencioni A, Schwarzenberg K, Brauer KM,
et al. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood. 2006;108(2):551-558.
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