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M. Gooptu and J. Koreth
lymphocytes.
Since the 1990s, standard of care (SOC) aGvHD prophy-
laxis has incorporated a CNI (e.g., tacrolimus [Tac], cyclosporine [CyA]) plus another agent (e.g., methotrexate [MTX]), mycophenolate mofetil [MMF], sirolimus [Siro]).22,23 CNI inhibit alloreactive T-cell proliferation and activation. However, even with CNI-based platforms, rates of grade II-IV aGvHD are 30-40%, with 10-15% severe grade III-IV aGvHD. Furthermore, CNI are associated with various toxicities (e.g., renal dysfunction, thrombotic microangiopathy [TMA]) which can add to transplant-relat- ed mortality (TRM). Hence novel prophylactic therapies with improved efficacy and less toxicity are of great interest in transplantation. Recent advances in aGvHD prevention, some of which are challenging the established CNI-based platform, are discussed below.
In vivo T-cell depletion/modulation
Anti-thymocyte globulin - ATG is the polyclonal purified
IgG fraction of sera from horses or rabbits immunized with human thymocytes or T-cell lines. In vivo T-cell depletion (TCD) with ATG has been extensively evaluat- ed to reduce the incidence of acute and chronic GvHD with HLA-matched as well as cord blood and haploHSCT.
In the CNI-era, four RCT evaluated CNI/MTX prophy- laxis ± ATG.24 In the first, using horse ATG, a reduction in aGvHD was offset by higher rates of infection with no difference in NRM or OS; however, there was a reduction in severe chronic GvHD.25,26 In the second, using rabbit ATG,27,28 and the third, mainly using PBSC grafts, there was no effect on aGvHD, with a reduction in cGvHD.29 These studies concluded that reduction in severe cGvHD with no deleterious effect on OS is a true ATG effect; however, aGvHD was not reduced. More recently, an RCT evaluated Tac/MTX ± anti T-lymphocyte globulin (ATLG) in MAC MUD HSCT, with a significant reduction in grade II-IV aGvHD and moderate/severe cGvHD. However, NRM and OS was impaired in the ATLG arm.30 A higher dose of ATLG in the trial may have contributed to increased infections and mortality.
In pioneering studies by Storek et al., persistence of ther- apeutic ATG levels on days +7 and +28 were found to reduce acute and chronic GvHD.31 There is also evidence that excessive persistence or dosing of ATG may have immunosuppressive toxicity with increased NRM and relapse. Individualized ATG dosing, based on absolute lymphocyte count beyond recipient weight, could be a way forward to control GvHD without impairing NRM and relapse.32
Post-transplant cyclophosphamide - the use of PTCy-based GvHD prophylaxis has been a major advance allowing the widespread use of haploHSCT with increasing impor- tance also in HLA-matched and mismatched HSCT.
Haplo-hematopoietic stem cell transplantation was ini- tially associated with increased graft rejection and GvHD due to strong bidirectional donor versus recipient alloreac- tive responses. HaploHSCT regimens utilized highly immunosuppressive conditioning with high transplant- associated toxicity. The innovative use of PTCy dosed at 50 mg/kg on days +3 and +4 following NMA haploHSCT resulted in a grade II-IV aGvHD rate of 34%, with a low grade III-IV aGvHD rate of 6% and a trend towards reduc- tion in severe cGvHD. Relapse rates were around 50%.33 Numerous subsequent studies replicated these results, and PTCy is now the most widely used haploHSCT regimen.
It is worth noting that overall aGvHD rates with PTCy, at 30-80%, are not necessarily lower than SOC, but severe aGvHD and cGvHD rates are lower.
PTCy was initially thought to act via depletion of allore- active T cells by elimination of proliferating cells and intrathymic clonal deletion of alloreactive T-cell precur- sors.34 More recent data suggest important roles for Treg preservation and Teff exhaustion as additional mecha- nisms of effect.34
PTCy has also been evaluated in alternative donor HSCT. In a phase II RCT of MUD/MMUD PBSC HSCT, three GvHD prophylaxis regimens were compared with SOC Tac/MTX: PTCy/Tac/MMF, Tac/MTX/bortezomib, and Tac/MTX/maraviroc. The primary 1-year GvHD free, relapse-free survival (GRFS) endpoint was improved in the PTCy-based arm.17 Interestingly, grade II-IV aGvHD was similar; however, impressive gains were seen for severe grade III-IV aGvHD. Chronic GvHD requiring immuno- suppression also fared much better with PTCy.
Recently, a small European RCT compared PTCy/Tac/MMF to CyA/MMF in HLA-matched RIC PBSC HSCT. Grade II-IV aGvHD was lower with PTCy (P=0.014) while severe grade III-IV aGvHD was 6% versus 12%, respectively.35 Importantly, CyA/MMF is considered inferior to Tac/MTX, and hence PTCy-based prophylaxis is being definitively evaluated in a large multi-center phase III RCT (BMT CTN 1703) of MUD PBSC RIC HSCT comparing PTCy/Tac/MMF with Tac/MTX.
Sirolimus - Siro is an mTOR inhibitor that synergizes with CNI in reducing Teff proliferation and activity. Siro inhibits CD8+ cells36 while promoting Treg proliferation in vitro,37 an attractive immunologic profile for GvHD preven- tion. Importantly, unlike CNI, it does not cause nephro- toxicity. Siro/MTX prophylaxis has been investigated in a large RCT of MAC HSCT, documenting similar grade II- IV but lower grade III-IV aGvHD compared to Tac/MTX.38 In RIC transplants, a phase II RCT showed that combined Siro/Tac/MTX had less grade II-IV aGvHD but no survival benefit.39 A recent phase III RCT of NMA HSCT conclud- ed that adding Siro to CyA/MMF was superior to CyA/MMF.40 Given that the combination of Tac and MMF is inferior to Tac/MTX in a phase II RCT in preventing grade II-IV aGvHD,41 and CyA has also been shown to be inferior to Tac in the past for GvHD prophylaxis, it is unclear how these data impact centers that primarily use Tac/MTX-based regimens. Although less nephrotoxic, Siro has also been associated with higher rates of veno- occlusive disease (VOD), particularly with ablative busul- fan and cyclophosphamide,42 and is avoided in patients at a higher risk for VOD. It has also been associated with increased rates of TMA, particularly in combination with CNI.43 Discontinuation of CNI typically resolves TMA in this setting.
Finally, the combination of Siro/PTCy as a CNI-free, less nephrotoxic regimen with acceptable rates of engraftment and aGvHD has been evaluated.44 This is currently reserved for scenarios precluding CNI use (e.g., sickle cell HSCT, with renal dysfunction). Given the Treg-sparing effect of Siro,45 novel combinations (e.g., with OX40L blockade) are being explored as GvHD prophylaxis platforms.46
Ex vivo T-cell depletion
A deeper understanding of transplant biology and the
availability of sophisticated clinical-grade cell separation technology underpins advances in graft manipulation
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haematologica | 2020; 105(11)