Robert Zeiser, MD

 After 4 decades of testing multiple approaches, we have now 3 approved drugs, which are ibrutinib, belumosudil, and ruxolitinib that were approved by the FDA for chronic graft-vs-host-disease [cGVHD] in the past 4 years, and ruxolitinib is also approved by the EMA [European Medicines Agency] for steroid refractory cGVHD. These developments are exciting, but there is still room for improvement. Oher exciting developments include regenerative approaches that are not immunosuppressive but rather target the regeneration, for example, of the damaged intestinal tract and what is also important is a better understanding of potential biomarkers and the involvement of the nonclassical GVHD.

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Closing out the program, Robert Zeiser, MD, shares what he is looking forward to in the field of graft-vs-host-disease.

Future Directions for GVHD

 They can induce diabetes, so we monitor the blood sugar in all patients, and we taper the corticosteroids rapidly. We also notice that some patients develop osteonecrosis and osteoporosis. We monitor bone density in all patients that receive high corticosteroids. We try to taper them in selected cases. We administer also base phosphonates particularly in those patients with fractures and we add vitamin D in these patients as well. Corticosteroids can also induce peptic ulcer disease. Thus, in patients receiving high dose steroids, we would also give a proton pump inhibitor that prevents the peptic ulcer disease. We control hypertension induced by corticosteroids. We try to avoid food retention. We [also] give some patients diuretics if they have strong food retention and we monitor infections because these patients are at higher risk for viral, fungal, bacterial infections so we give prophylaxis for herpes simplex virus, for fungal infections ... For other immunosuppressive approaches besides corticosteroids, we monitor in particular the infectious complications also in patients receiving MMF [mycophenolate mofetil], everolimus, imatinib, or rituximab. It is very important to understand that these are immunosuppressive approaches where viral, fungal and bacterial infections need to be monitored and patients should receive prophylaxis.

Adverse events related to chronic graft-vs-host-disease therapies and strategies to manage these adverse effects are considered. 

Adverse Events From cGVHD Therapies

 Besides ruxolitinib, ibrutinib, and belumosudil, there are several other commonly used treatment options for …chronic graft-vs-host-disease [cGVHD], those include for example extracorporeal photopheresis. For this intervention, called ECP, the presence of a venous access catheter is required. This treatment has a good safety profile and it was shown that it reduces the use of corticosteroids. Patients with cGVHD that have had steroids can also receive calcineurin inhibitors [CNIs]. It was shown that CNIs reduce the use of corticosteroids and the adverse effects are, in particular, renal impairment and hypertension. In patients failing corticosteroids, we can also use mTOR inhibitors, such as sirolimus or everolimus, and they are sometimes combined with CNI inhibitors which increase the risk of endocellular damage so called TMA [thrombotic microangiopathy]. They can lead to thrombocytopenia and they interfere with wound healing. MMF [mycophenolate mofetil] was also shown to reduce the use of corticosteroids but it increases the risk of reactivation and relapse. In itself, MMF can induce colitis which can mimic cGVHD of the GI [gastrointestinal] tract.

Robert Zeiser, MD, touches on additional therapeutic options for steroid-refractory chronic graft-vs-host-disease, such as extracorporeal photopheresis, mycophenolate, everolimus, and more.

Additional Therapy Options for Steroid-Refractory cGVHD

 Ibrutinib is a selective and irreversible inhibitor of Bruton tyrosine kinase, BTK, which is a nonreceptor tyrosine kinase which belongs to the TEC family of kinases. It is mainly expressed in B-cells and not that much in other cells in particular; not in T-cells or in K-cells. It inhibits signaling downstream of the B-cell receptor and therefore blocks B-cell activation. Ibrutinib also blocks I2 [interleukin-2] inducible kinase, ITK, and ITK controls proximal TCR [T-cell receptor] signaling and thereby also ibrutinib is not inhibiting B-cells alone but also interferes with NF kappa B [nuclear factor kappa B] and MOB [Mps 1 binder co-activator proteins] kinase signaling T-cells. This drug, ibrutinib, was tested in adult patients with chronic graft-vs-host-disease [cGVHD] that had failed first line systemic therapy, and this was a phase 1/2 open label multicenter trial. Here in this trial, the primary efficacy end point was best cGVHD overall response rate [ORR]. Of note inflammatory skin or mouth involvement was a requirement to be enrolled, and in this trial 42 patients with cGVHD were enrolled. The ORR was 67 %with a complete response [CR] rate of 21 and a partial response [PR] rate of 45%. Based on these promising results, ibrutinib was approved by the US FDA in August 2017 after failure of 1 or more lines of systemic therapy for GVHD.

Ruxolitinib is a TKI that targets the JAK1/JAK2. JAK1/2 mediate downstream effects of multiple cytokines including the IL-2 [Interleukin 2 protein] receptors, the IL-6 receptor, interferon gamma, IL-7 or IL-15 receptor as well as other common gamma chain cytokine receptors.

To test ruxolitinib for cGVHD at randomized open label multicenter clinical trials, ruxolitinib compared with best available therapy [BAT] was performed and this trial included patients with corticosteroid refractory or dependent cGVHD. The trial was called the REACH3 trial [NCT03112603]. This randomized trial involved 329 patients that were randomly assigned 1:1 to receive either ruxolitinib 10 mg twice daily or 1 of 10 possible investigator selected BATs. ORR was higher in the ruxolitinib group compared with the BAT group at week 24. The median failure-free survival was longer in the ruxolitinib group compared with the control group with more than 18.6 months vs 5.6 months and a higher symptom response was observed according to the modified symptom scale in the ruxolitinib arm compared with the BAT arm with 24% vs 11%. Based on these results in September 2021, the FDA approved ruxolitinib 10 mg twice daily for cGVHD disease after failure of 1 or 2 lines of systemic therapy for cGVHD in adult patients and pediatric patients aged 12 years or older.

Belumosudil is a first-in-class selective inhibitor of Rho-associated coiled-coil containing protein kinase 2, ROCK2 [Rho kinase 2] and this kinase ROCK2 is activated downstream of cytokines and growth factor receptors as well as … and it inhibits the production of pro-inflammatory cytokines in particular IL-21 and IL-17. To test the efficacy of this ROCK inhibitor, belumosudil, patients were included into phase 1/tw2o trial. This was an open label dose finding study of belumosudil and it enrolled 54 patients with chronic GVHD that had to receive 1 to 3 prior lines of therapy. Here, the investigators measured the best overall response of belumosudil, l and they observed that giving belumosudil at a dosage of 200 mg daily led to a response of 74%, [and] 200 mg twice daily had a response of 77%. Thus, based on these results, belumosudil 200 mg daily was approved by the FDA in July 2021 for adults and pediatric patients aged 12 years or older with cGVHD after failure of at least 2 prior systemic therapy lines.

Therapies for steroid-refractory chronic graft-vs-host disease, ibrutinib, ruxolitinib, and belumosudil, are explored in a comprehensive analysis.

Treatments for Steroid-Refractory cGVHD

 First-line treatment for chronic graft-vs-host disease [GVHD] depends on the severity of the chronic GVHD. For the more severe forms and moderate or severe chronic GVHD, systemic corticosteroids are recommended at a dose of 0.5 to 1 mg/kg of body weight. The challenges of this treatment are that first, some patients—40% to 50%—don’t respond and need a second-line treatment. Steroids induce a lot of adverse effects, including weight gain, edema, diabetes, infections, hypertension, and aseptic bone necrosis. As you can see, there are a lot of adverse effects of this treatment, so it’s desirable to treat as short as possible.

Glucocorticoid-resistant or -refractory acute GVHD is defined as a disease that progresses by day 5 or has no response to treatment by day 7 to the treatment. It has a dose of 2 mg/kg body weight of prednisolone or equivalent other corticosteroids, and the dose is typically divided. For chronic graft-vs-host disease, corticosteroids are given for at least 2 weeks with a dose of 1 mg/kg body weight, and there is progression or no response within this time. At a dosage of 0.5 mg/kg body weight for 4 to 6 weeks, there’s no response or ability to taper the corticosteroids below a dosage of 0.5 mg/kg body weight over 8 weeks.

A GVHD expert comments on the frontline therapy available for the condition.

Chronic GVHD First-Line Therapy

 The prophylaxis regimen that I apply to my patients depends on the type of transplants we have. In a patient with a matched related donor, we highly recommend a calcineurin inhibitor combined with antimetabolite. In contrast, in patients with an unmatched nonrelated donor, I’d add ATG [anti-thymocyte globulin] to this conditioning or post-transplant cyclophosphamide. For haploidentical transplantation, I’d always add post-transplant cyclophosphamide to the conditioning because it was clearly shown that this reduces the risk of acute graft-vs-host disease [GVHD].

Chronic graft-vs-host disease is a syndrome of variable clinical features that shares features of autoimmune diseases and other immunological disorders—for example, scleroderma or Sjögren syndrome and primary biliary cirrhosis or bronchiolitis obliterans. The clinical manifestations may be widespread and are possibly involving only certain organs. The primary clinical manifestations are skin involvement: local sclerosis or systemic sclerosis with culture in the position, hardening of the skin, and dry or a mucosa gastrointestinal tract … and sclerosis, which can lead to difficulties for the patients to swallow and elevated liver values in particular bilirubin or transaminase, as well as bronchiolitis obliterans syndrome, which are possibly connected to severe lung GVHD, which clearly reduces the quality of life of patients to the reduced physical fitness.

Selection of prophylaxis regimen is reviewed followed by a discussion of the typical patient presentation of GVHD.

Robert Zeiser, MD | Authors

Articles

Future Directions for GVHD

Adverse Events From cGVHD Therapies

Additional Therapy Options for Steroid-Refractory cGVHD

Treatments for Steroid-Refractory cGVHD

Chronic GVHD First-Line Therapy

GVHD Prophylaxis and Patient Presentation