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Associate Professor of Medicine
Harvard Medical School
Medical Director, Stem Cell Transplantation
Dana-Farber Cancer Institute
Corey S. Cutler, MD, MPH, FRCPC, has disclosed that he has received consulting fees from Elsalys, Fresenius, Genentech, Generon, Incyte, Jazz, Kabi, Kadmon, Medsenic, Omeros, and Pharmacyclics.
Graft-vs-host disease (GVHD) is a severe complication often observed after allogeneic hematopoietic stem cell transplant, when the donor bone marrow contains immunologically competent cells that attack the recipient. Depending on timing of onset and clinical manifestations, GVHD can be acute (aGVHD) or chronic (cGVHD). Corticosteroids are the standard first-line treatment, but prolonged use is associated with toxicities and drug resistance. For patients with steroid-refractory GVHD, there are 2 FDA-approved treatments: ruxolitinib, for steroid-resistant aGVHD, and ibrutinib, for patients with cGVHD that failed ≥ 1 lines of therapy. There is currently a strong unmet need for new GVHD treatment options, and many emerging treatments are being tested.
Presenters at the recent Transplantation & Cellular Therapy (TCT) Meetings in Orlando, Florida, introduced results from a number of studies of patients with GVHD that may have promising clinical implications. I discuss the key takeaways below.
ROCKstar Study: KD025 in Patients With cGVHD
Perhaps the most clinically significant results were from the planned interim analysis of the ROCKstar study that I and my colleagues presented. This study is a pivotal, open-label phase II randomized trial testing 2 different dose levels of KD025 in patients with cGVHD after ≥ 2 previous lines of systemic therapy. KD025 is an inhibitor of ROCK2; previous data from the phase IIa KD025-208 study showed clinical activity with KD025 in patients with cGVHD, with an ORR of 65%, and good tolerability.
In ROCKstar, 132 patients (median age: 56 years) with steroid-refractory cGVHD after a median 4 lines of systemic therapy were randomly assigned to KD025 200 mg QD (n = 66) or 200 mg BID (n = 66). Two thirds of these patients had severe cGVHD, 52% with involvement of ≥ 4 organs. Approximately one third of patients had received previous ibrutinib therapy, and the median prednisone dose for both arms was 0.2 mg/kg/day.
Interim results at a median follow-up of 5 months showed that the ORR was statistically significant and essentially equivalent for the 200 mg QD and 200 mg BID groups, at 64% (95% CI: 51% to 75%) and 67% (95% CI: 54% to 78%), respectively. These results are also equivalent to the 65% ORR from the KD025-208 study, which is a positive showing of consistency for the agent. Even patients with previous ruxolitinib and ibrutinib therapy achieved ORRs > 50%. Toxicity was similar between the groups, with fatigue, diarrhea, and nausea the most common adverse events, all higher in the QD cohort. The FDA has granted KD025 Breakthrough Therapy Designation and Orphan Drug Status. These results, although preliminary, are very promising for this agent, which is the first drug developed expressly for the treatment of cGVHD. I look forward to additional study results for KD025 in this challenging patient group.
Sirolimus vs Calcineurin Inhibitors in Posttransplantation
Another interesting study was presented by Bejanyan and colleagues that examined a strategy to replace calcineurin inhibitors with sirolimus as posttransplant prophylaxis in patients with peripheral blood haploidentical hematopoietic cell transplantation. In this phase II study of 32 patients with hematologic malignancies (one half with acute myeloid leukemia), patients were treated with sirolimus in place of calcineurin inhibitors plus posttransplant cyclophosphamide and mycophenolate mofetil after undergoing peripheral blood hematopoietic cell transplantation. The primary endpoint was a reduction of cumulative grade 2-4 aGVHD at Day 100 after transplant from the historical benchmark of 40% down to 20%. Although it was a small study, results at a median of 15.4 months were promising, with a grade 2-4 rate of 18.8% for aGVHD and a very low rate of 20% at 1 year for cGVHD. These are important data, showing that replacing calcineurin inhibitors with sirolimus as prophylaxis may show efficacy while lowering risk of both acute and chronic GVHD.
Topical Progesterone for Ocular cGVHD
Most patients with cGVHD exhibit ocular manifestations that can have a severe impact on quality of life. A randomized (2:1), double-blind phase II study by Luo and colleagues examined the efficacy of topical progesterone in 33 adult patients with moderate to severe ocular cGVHD. Patients self-applied a 1% progesterone gel or placebo to their forehead BID for 10 weeks. Study endpoints were patient-reported symptoms and physician-reported ocular tear film and surface staining. Results in the progesterone group showed significant reduction in interior and central, but not superior, cornea staining. Patient-reported reductions in global score (-25.87 vs +1.04; P = .0006), symptom frequency (-30.72 vs -2.18; P = .0002), and severity (-19.82 vs +1.64; P =.0048), based on the Symptom Assessment Questionnaire in Dry Eye, were all significantly superior in the progesterone cohort. These results are extraordinarily promising, and likely will be followed up with phase III studies.
Sitagliptin Prophylaxis for aGVHD
Farag and colleagues reported on an interesting trial using the type 2 diabetes drug sitagliptin, a DPP-IV (CD26) inhibitor, as prophylaxis after allogeneic peripheral blood stem cell transplant. This is work that has been developed for some time, but this was the first time we have seen this abstract. The team had observed from an earlier trial that patients treated with sitagliptin for enhancement of cord blood engraftment showed a lower than expected rate of aGVHD.
To test this outcome, researchers conducted a prospective phase II trial of 36 posttransplant patients treated with sitagliptin plus tacrolimus and sirolimus, with a primary endpoint of grade 2-4 aGVHD at Day 100 compared with the historical rate of 30%. By Day 100, aGVHD occurred in only 2 of 36 patients (5.6%), 1 grade 2 and 1 grade 4. At 12 months, relapse-free survival was 77.2% and OS was 94.3%. Toxicities through Day 30+ included grades 3/4 mucositis (n = 15), viral reactivation/infection, acute kidney injury (4 of 5 with high tacrolimus levels), and passenger lymphocyte syndrome. Overall, the responses were promising and the regimen was reasonably well tolerated.
Three years ago, we had no approved treatments specifically for GVHD. We now have ibrutinib and ruxolitinib and the potential approval of a third drug, KD025, in the GVHD space in the near future. This is an extraordinarily exciting time for clinicians treating patients at risk for GVHD.
What are your biggest challenges in managing GVHD? I encourage you to answer the polling question and join the conversation in the discussion box below.