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Let’s now discuss managing cGVHD. Revisiting our second case, we have a 45-year-old woman with CLL treated with venetoclax and obinutuzumab who now has multisystem cGVHD, which occurs 9 months after reduced-intensity conditioning transplant. She’s been on prednisone at a dose of 40 mg QD (or roughly 0.5 mg/kg) for the past 8 weeks, and tacrolimus in the therapeutic range. What treatment would you recommend next for this patient? My choice would be the BTK inhibitor ibrutinib, and I will discuss why in this section.
Which organs are involved in cGVHD? cGVHD is much more heterogeneous than aGVHD. The skin, the mouth, the liver, the eye, the GI tract, and otherorgans are all potentially involved in cGVHD. The disease is much more variable, and we often say that no 2 individuals look alike in this disease.
This slide shows a few of the manifestations of severe cGVHD. You see terrible oral disease and skin disease, including lichenification of the mouth, and severe scleroderma of the skin.
Unfortunately, even with steroids, results for cGVHD are less successful than for aGVHD. Up to 80% of patients will progress within their first year after initiating frontline therapy for cGVHD. This slide shows the likelihood of failure over time. On the left, the table shows failure-free survival (FFS) rates in patients in a large (N = 575) prospective cGVHD trial, dropping from 45% at 1 year to 11% at 4 years.
The graph shows results from 2 prospective, multicenter, observational studies, with the percentage of patients with an FFS index ≤ 0 (n = 231) shown on the top line, and those with an FFS index > 0 on the bottom line. We see that even individuals who are predicted to do well still have an extraordinarily high failure rate after their initial therapy. 
The challenge of treating newly diagnosed cGVHD is shown with this list of phase III trials of patients with this disease, all of which had negative results.
Two potential approaches to managing cGVHD are to inhibit alloreactive B-cells in cGVHD or to upregulate the regulatory T-cells in cGVHD, because these are thought to be the immunologic brakes that can prevent or treat GVHD.
So how do we choose the right treatment? Steroids was the standard choice, with mycophenolate mofetil, tacrolimus, cyclosporine, or ECP as reasonable options. However, with the approval of ibrutinib for patients in this setting, that changes the treatment dynamic. It depends on what agent you are experienced with, what organ toxicities the patient currently has and what other adverse events you want to avoid, and the ease of administration of the given agent. Some patients only want pills, whereas others would rather have intensive IV therapy and be done with it sooner rather than later. All of these considerations factor in to how we use these second-line therapies.
The BTK pathway is another target for cGVHD therapy. My colleagues and I studied the effects of the BTK inhibitor ibrutinib in a multicenter, open-label trial in patients (N = 42) with steroid-refractory cGVHD. The ORR was 67% (28/42 patients), with 9 patients having a CR and 19 having a PR. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. As a result of this trial, ibrutinib was granted FDA approval as the only approved treatment of steroid-refractory cGVHD.
With the success of ibrutinib in steroid-refractory cGVHD, a large phase III trial was developed to study ibrutinib plus corticosteroids for new-onset cGVHD. iNTEGRATE is a multinational phase III trial involving 186 patients randomized to receive ibrutinib plus prednisone or placebo plus prednisone as their initial therapy for cGVHD. The primary endpoint is ORR at 48 weeks. The study is currently ongoing, and we are eagerly awaiting results.
One therapy that has been used for many years is ECP. Currently, ECP in combination with corticosteroids is not considered a standard frontline treatment. To examine this, researchers performed a randomized, phase I study of the addition of ECP to standard-of-care corticosteroids in the initial treatment of cGVHD. The primary endpoint was ORR at Week 28 in the intention-to-treat population. Results showed a possible advantage with the combination, with a Week 28 ORR of 74.1% for standard of care plus ECP vs 60.9% for standard of care.
Another potential therapeutic target in cGVHD is the B-cell pathway. My colleagues and I performed a trial that treated 21 individuals with rituximab for 4 weeks that resulted in an ORR of 70% at 1 year. The figure on the right shows outcomes from other trials that studied rituximab in cGVHD, with ORRs from 50% to 83% and a combined response rate of 66%.
Low-dose IL-2 has also been tested for cGVHD. The rationale for this study is that low-dose IL-2 can increase the proliferation and maintain the life of regulatory T-cells, which are deficient in cGVHD. In one of the few studies of IL-2 in this disease, patients with cGVHD were given low-dose subcutaneous IL-2 daily for 12 weeks, resulting in an ORR of 61%, all PRs, with responses in multiple organs ranging from 17% to 46%.
We know that ruxolitinib is effective in aGVHD, so the question is, will it work for cGVHD? A retrospective study was conducted by Zeiser and colleagues in patients with moderate to severe cGVHD (N = 41) treated with ruxolitinib outside the confines of a clinical trial. An ORR of 85% was achieved. Although it was retrospective, what was important in this study was that the relapse rate was low at 5.7%, and the responses occurred promptly after initiation of cGVHD therapy.
Those promising outcomes led to the initiation of a large (N = 330), randomized phase III REACH3 study, which is comparing ruxolitinib to standard or physician's-choice therapy for patients with steroid-refractory cGVHD. This is a pivotal trial in our field that has completed patient accrual and is ongoing.
Let’s return to our second case.
Back to our second case, we have a 45-year-old woman with CLL treated with venetoclax and obinutuzumab who now has multisystem cGVHD, which occurs 9 months after reduced-intensity conditioning transplant. She’s been on prednisone at a dose of 40 mg QD (or roughly 0.5 mg/kg) for the past 8 weeks, and tacrolimus in the therapeutic range. After our previous discussion, what treatment would you recommend next for this patient? As I mentioned earlier, my choice would be the BTK inhibitor ibrutinib, for a few reasons: Ibrutinib is the only treatment approved by the FDA for steroid-refractory cGVHD, and because this patient has CLL, the use of ibrutinib may also help maintain her response. The other options are reasonable to consider, but ibrutinib is the best choice for this patient.
A promising investigative therapy for cGVHD is the ROCK2 inhibitor KD025. KD025 has been tested in 2 phase II studies The study design for the first phase II study, shown on this slide, had 3 successive cohorts of patients (N = 54) treated with KD025: 200 mg QD, 200 mg BID, and 400 mg QD.
ORR for the 3 cohorts ranged from 52% to 65%, with an ORR of 59% in the intention-to-treat population. Of interest, the ORR was similar regardless of morbidities, including severe GVHD, multiple lines of therapy, and/or multiple-organ involvement.
The phase II ROCKstar study is a pivotal, open-label, randomized trial testing 2 different dose levels of KD025 in patients (N = 132) with cGVHD after 2 to 5 previous lines of systemic therapy. Two thirds of these patients had severe cGVHD, 52% of them with involvement of ≥ 4 organs.
Planned interim analysis results were announced at the February 2020 Transplantation & Cellular Therapy (TCT) Meetings. At a median follow-up of 5 months, the ORR was statistically significant and 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. 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.
There were other GVHD studies of interest presented at TCT; here are a few of the most noteworthy. (For additional Clinical Care Options coverage of GVHD studies presented at TCT 2020, please see this commentary.) A phase II study in 33 adult patients with moderate to severe ocular cGVHD showed that using self-administered 1% topical progesterone gel to their forehead BID for 10 weeks resulted in statistically significant improvements in clinical cornea staining as well as patient-reported quality of life scores.
In another study, researchers tested the DPP4 (CD26) inhibitor sitagliptin combined with tacrolimus and sirolimus as prophylaxis in a phase II trial of 36 posttransplant patients. By Day 100, aGVHD occurred in only 2 of 36 patients (5.6%) vs the historical rate of 30% with standard treatment.
An open-label phase II study in 27 patients with grade 2-4 lower-GI aGVHD postallogeneic SCT found that F-652 (an IL-22 dimer) combined with corticosteroids showed a 28-day response of 70% in lower-GI aGVHD.
Lastly, a phase II study examined a strategy to replace calcineurin inhibitors with sirolimus as posttransplant prophylaxis in patients receiving post-transplant cyclophosphamide with peripheral blood haploidentical HCT. Patients (N = 32) were treated with sirolimus in place of calcineurin inhibitors plus posttransplant cyclophosphamide and mycophenolate mofetil after HCT. At a median of 15.4 months, the grade 2-4 rate was 18.8% for aGVHD and 20% at 1 year for cGVHD.
Before 2017, there was no FDA-approved treatment specifically for GVHD. We now have ruxolitinib for aGVHD and ibrutinib for cGVHD, with exciting new data forthcoming with the REACH3 and iNTEGRATE trials, respectively. Add to that the positive results of KD025 and other novel agents for GVHD treatment, and clinicians have increasingly promising options to offer their patients with GVHD.