For Patients Facing Chronic GVHD, 2022 Was a Breakthrough Year

Chronic GVHD (cGVHD) is a dark cloud at the edge of allogeneic hematopoietic cell transplant (allo-HCT) that for some patients, breaks into a storm. Despite increasing awareness, nobody knew quite what to do with this pesky, and at times highly dangerous, doppelgänger of graft-versus leukemia (GVL). Well, the time has finally come for us, the transplant community, to say “no more” to this feared complication. As of 2023, we will not only have several U.S. Food and Drug Administration (FDA) –approved, highly active oral agents to combat active steroid-dependent or -resistant cGVHD, but at last we will have demonstrated that cGVHD can be prevented with both simple (post-transplant cyclophosphamide [PTCy]) and complex (graft engineering) maneuvers, without increasing disease relapse.

With the 2017 FDA approval of ibrutinib for steroid-dependent/-resistant cGVHD,¹  the stage was set for an explosion of novel oral kinase inhibitor therapies for this disease. On the heels of the ibrutinib approval came the results of the ROCKSTAR study, a phase II multicenter trial evaluating belumosodil, a novel inhibitor of the rho-associated coiled-coil-containing protein kinase-2 (ROCK2). Activation of ROCK2 promotes proinflammatory cytokines and inhibits regulatory T cells, while also aiding collagen deposition and fibrosis. Inhibiting this pathway is thus compelling, particularly for sclerotic cGVHD. In the ROCKSTAR cohort of heavily pretreated patients with cGVHD who were randomized to daily or twice-daily dosing of this oral agent, overall response rate was 74 to 77 percent, with symptom improvement in 59 to 62 percent, including among patients previously treated with ibrutinib.²  Striking improvements in organ-based assessments were noted, particularly among patients with lung and liver cGVHD. Considering these results, belumosodil became the second oral kinase inhibitor to receive FDA approval for cGVHD. Around the same time, the results of REACH3, a randomized phase III trial of ruxolitinib versus best available therapy, were published.³  In this registration trial for patients with advanced cGVHD, treatment with ruxolitinib was associated with a doubling of response (49.7% vs. 25.6) and failure-free survival (>18.6 vs. 5.7 months), relative to best available therapy. In late 2021, patients and providers celebrated when ruxolitinib became the third oral kinase inhibitor to be awarded FDA approval for the treatment of cGVHD.

The availability of effective agents to treat active cGVHD is a clear step forward, but when it comes to GVHD, it is certainly true that “an ounce of prevention is worth a pound of cure.” In this sense, the field may have no greater breakthrough than the overly simple, yet highly effective incorporation of PTCy into the allo-HCT platform. As discussed in a recent Diffusion article in The Hematologist,⁴  although the BMT CTN 1301 trial of PTCy following myeloablative conditioning did not demonstrate superiority relative to standard tacrolimus/methotrexate in reducing cGVHD, outcomes were equivalent, prompting many centers to shift practice to standard use of PTCy in the myeloablative, matched-donor setting.⁵  In patients receiving reduced-intensity conditioning (RIC), the highly anticipated results of BMT CTN 1703, presented as a Late-Breaking Abstract at this year’s ASH annual meeting, have likely confirmed PTCy as the new standard of care. Not only were cGVHD rates lower in patients receiving PTCy (plus tacrolimus/mycophenolate) as opposed to those receiving standard tacrolimus/methotrexate, but one-year GVHD-free relapse-free survival (GRFS) was significantly higher (53% vs. 35%), with no increase in relapse. Also in the past year, the utility of PTCy to overcome the HLA barrier in the mismatched unrelated donor (MMURD) setting was proven. In a phase II study conducted by the National Marrow Donor Program, patients receiving either myeloablative conditioning or RIC followed by MMURD bone marrow graft, PTCy, and tacrolimus/mycophenolate had unbelievably low rates of cGVHD (18% severe cGVHD for myeloablative and 0% for RIC).⁶  This trial was equally groundbreaking in that this approach allowed for substantially greater numbers of patients from non-White and/or Hispanic racial/ethnic groups (48% of study participants) to receive allo-HCT. The National Marrow Donor Program recently launched the ACCESS trial (NCT04904588) to study this platform in the MMURD setting using peripheral blood stem cell grafts.

At a time when simplistic maneuvers to reduce cGVHD are gaining traction, sophisticated technologies and rapid growth in the field of cellular therapy has allowed for marked advancements in donor graft engineering. One such approach has been depletion of donor alloreactive naïve T-cell, a technique that has been evaluated in three phase II trials in both adults and children, with very impressive reductions in three-year cGVHD (<10 percent) and improvement in GRFS (64%).⁷  Another interesting strategy was demonstrated with OrcaBio’s Precision-T, a CD34+ selected donor graft with the addition of regulatory T cells and conventional T cells administered in a 1:1 ratio. Results of this strategy in the myeloablative setting were presented at the 2022 Annual Meeting, with rates of grade 3 or higher acute GVHD and moderate to severe cGVHD of five percent and six percent, respectively.⁸  Importantly, this technology seems to be scalable across the United States, with a donor-to-recipient “vein-to-vein” time of less than 72 hours.

This has truly been a breakthrough time for cGVHD, yet we have so much more to do. We must continue to aim for higher and higher rates of GRFS in allo-HCT, supplemented by patient-reported outcomes and validated GVHD symptom scores. As in all of hematology, our therapeutics are too expensive, and future studies should incorporate cost effectiveness analyses and mechanisms to address and expand access to care, as this astonishing progress is only meaningful if we can reach all patients in need. Have we truly conquered the holy grail of allo-HCT? Perhaps not entirely, but we are certainly getting closer.