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Organ specific efficacy
First-line treatment for chronic graft-versus-host disease (cGvHD), which consists of steroids, has not changed much over the last three decades. In the case of severe cGvHD, another immunosuppressant may be added to reduce the use of steroids. Recently, triple combinations with mycophenolate mofetil have also been used. Historically, agents such as pentostatin, etanercept, sirolimus, and monoclonal antibodies have been used to treat GvHD in second-line/refractory settings.1
Ibrutinib is the only agent approved for the treatment of adult patients with cGvHD who have failed ≥ 1 line of systemic therapy. The U.S. Food and Drug Administration (FDA) approval of ibrutinib in 2017 was based on a small (N = 42), single-arm, multicenter study in patients with cGvHD who received one to three prior treatments. Overall, the trial reported a 69% response rate (31% complete response; 38% partial response), and these responses were maintained for > 10 months in the majority of patients.2
Once cGvHD occurs, most patients require prolonged treatment with multiple lines of therapy. Therefore, more approved treatment options are urgently needed. Here we report the agents that are under investigation for the treatment of cGvHD.2
A number of recruiting or active, not recruiting trials are evaluating different agents for the treatment of cGvHD (Table 1).2
Table 1. Agents under investigation for the treatment of cGvHD*
Baricitinib, ruxolitinib, itacitinib
B cell/BCR signalling inhibition
Ibrutinib, acalabrutinib, ofatumumab, obinutuzumab
Co-stimulatory receptor blockade
Inhibition of donor macrophages
Mesenchymal stem cells
Regulatory T cells
IL-2, ECP +/- IL-2, efavaleukin alfa, expanded regulatory T cells
Nintedanib, alvelestat, topical ruxolitinib, topical dexamethasone, leflunomide
BCR, B-cell receptor; cGvHD, chronic graft-versus-host disease; ECP, extracorporeal photopheresis; IL-2, interleukin-2; IMiD, immunomodulatory drug.
Ruxolitinib, a JAK1/2 inhibitor, is under investigation in steroid refractory (SR) cGvHD. The REACH3 trial (NCT03112603) is a phase III, randomized trial investigating ruxolitinib against the best available therapies for patients (N = 329) with SR cGvHD. The primary results, reported by Robert Zeiser at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, showed a significantly higher overall response rate (ORR) with ruxolitinib versus best available therapy, a significant improvement in patient-reported symptoms and in failure-free survival, and a higher rate of best overall response. The FDA approval is pending.1,2
Baricitinib, another JAK1/2 inhibitor, is under investigation in therapy-refractory cGvHD (N = 20; with sclerotic skin cGvHD in 90% of patients). Early phase I/II (NCT02759731) results, presented by Noa G. Holtzman at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, showed that baricitinib was well tolerated with an ORR of 65% at 6 months.1
Itacitinib is a JAK1 inhibitor under evaluation in the phase II/III GRAVITAS-309 study (NCT03584516) in combination with corticosteroids as first-line treatment for moderate or severe cGvHD. After a first part of dose determination and dose expansion, the second part of the study will evaluate itacitinib (at the recommended dose from part one) or placebo administered in combination with corticosteroids. The primary endpoint will be ORR at 6 months.2
Belumosudil is a selective ROCK2 inhibitor under investigation in the phase II ROCKstar study (NCT03640481). This study is evaluating the safety and efficacy of once daily (n = 66) or twice daily (n = 66) belumosudil (200 mg) in patients with active cGvHD who received two to five prior lines of systemic cGvHD therapy. Updated top-line results, reported by Corey Cutler at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, showed that belumosudil achieved clinically meaningful and statistically significant ORRs in both arms.1
Ibrutinib is under evaluation in combination with corticosteroids in patients with new onset cGvHD in the phase III iNTEGRATE trial (NCT02959944).1
Acalabrutinib is a Bruton’s tyrosine kinase inhibitor that is more potent and selective than ibrutinib. It is already approved for relapsed/refractory mantle cell lymphoma and for chronic lymphocytic leukemia, and it is currently under investigation in a phase II trial (N = 50) at the dose of 100 mg orally twice daily. The primary endpoint will be the best ORR.2
Abatacept, a recombinant soluble fusion protein that inhibits T-cell activation via blockade of co-stimulation, is being investigated in a phase I study (N = 16; NCT01954979) for the treatment of SR cGvHD. Results from this study showed that abatacept is effective, with a clinical response in 44% of patients, and is well-tolerated. In addition, its use led to a reduction in prednisone usage in clinical responders by 51.3%. A phase II study is ongoing.
Axatilimab blocks colony stimulating factor 1 receptor leading to a depletion of circulating non-classical monocytes. It also prevents the differentiation and survival of M2 macrophages in tissue. Axatilimab is under investigation in a phase I/II study in patients with active cGvHD after at least two prior treatments. Preliminary phase I results, presented by Mukta Arora at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, showed good tolerability and deep and sustained responses across several organ systems.2
Pomalidomide is an immunomodulatory drug already approved for the treatment of multiple myeloma. In a phase II trial (N = 34; NCT01688466) the drug was shown to be effective in patients with moderate to severe cGvHD who were refractory to prior therapies.
Ixazomib is an orally available proteasome inhibitor that has been evaluated in a phase II trial (NCT02513498) in patients with cGvHD who failed at least one prior line of systemic immune suppressive therapy. Results showed significant improvements in the treatment failure rate with a good safety profile.
Glasdegib is a potent and selective oral inhibitor of the Hedgehog signalling pathway that is already approved in combination with low-dose cytarabine for newly diagnosed AML. It is under investigation in a phase I/II study (N = 20) at the dose of 50 mg orally daily. The primary endpoint will be best ORR.2
Mesenchymal stem cells (MSCs), a form of multipotent adult stem cells that can be isolated from bone marrow, adipose tissue, and cord blood, are under investigation in cGvHD in a number of studies. Completed studies include NCT01222039, which demonstrated that the use of adipose tissue-derived MSCs, in combination with immunosuppressive therapy, in patients (N = 14) with moderate or severe cGvHD is feasible with a good safety profile.3 In addition, bone marrow-derived MSCs for cGvHD are under investigation as monotherapy (NCT00361049, NCT01318330, NCT04189432) or in combination with glucocorticosteroids and cyclosporin (NCT04692376). Furthermore, MSCs cultured from umbilical cord blood are studied for dry eye symptoms in patients with cGvHD (NCT04213248).
The combination of expanded regulatory T cells plus ruxolitinib has also been investigated in cGvHD with the aim of improving responses. A trial investigating this combination in patients with SR cGvHD showed a good safety profile, with clinical improvement and a reduction in the use of immunosuppressive agents.
Efavaleukin alfa, an interleukin-2-mutein-Fc fusion protein (mutein), is under investigation in a phase I/II trial (NCT03422627) in patients with SR cGvHD. The drug is administered subcutaneously every 1 to 2 weeks and the primary endpoint is best ORR.2
More treatment options, which are better tolerated and more effective, may soon be available for the treatment of cGvHD. With the approval of novel agents, it will be important to understand how to personalize cGvHD treatment and how to sequence or combine agents correctly.
ASH 2020: Highlights for GvHD
GvHD Hub Chair Mohamad Mohty, Hôpital Saint-Antoine and Sorbonne University, Paris, FR, provides the highlights for GvHD from the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.
Key publications selected by the GvHD Hub Steering Committee
The GvHD Hub has worked closely with its Steering Commitee members to indentify key publications on acute and chronic GvHD fo you to download and use.
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