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Expert Takes on Key Questions in GVHD

Corey Cutler, MD, MPH, FRCPC

Associate Professor of Medicine
Harvard Medical School
Medical Director, Stem Cell Transplantation
Dana-Farber Cancer Institute
Boston, Massachusetts

Corey Cutler, MD, MPH, FRCPC, has disclosed that he has received consulting fees from CareDx, Fresenius Kabi, Incyte, Janssen, Jazz, Kadmon, and Mesoblast and other financial or material support from Omeros.

View ClinicalThoughts from this Author

Released: May 4, 2022

Clinical Care Options recently hosted a live webinar with stem cell transplantation experts Corey Cutler, MD, MPH, FRCPC; David Miklos, MD, PhD; and Robert Zeiser, MD, on the optimal management of patients with graft-vs-host disease (GVHD). In this commentary, the faculty address key questions asked by webinar participants regarding the treatment of patients with GVHD.

How do you treat patients with severe lower gastrointestinal acute GVHD who are progressing on ruxolitinib? 

Robert Zeiser, MD:
These patients are hard to treat and they have a high mortality if they are refractory. If a patient doesn’t respond by this point and is still on corticosteroids, there is no benefit to keeping this treatment, so we taper the steroids in order to at least reduce their side effects, and we start with extracorporeal photopheresis in these patients. We have other treatment options such as everolimus, and I hope that we will soon have other novel options such as the regenerative approaches interleukin‑22 or glucagon-like peptide–2, because in my view, by this point, we have already inhibited the immune response effectively with multiple drugs, steroids, and ruxolitinib. Now we have severe tissue damage that we need to overcome, which should be our main task rather than adding more immunosuppressive interventions.

David Miklos, MD, PhD:
In patients who’ve now been on therapy for 4 weeks and, again, have risk for viral reactivation, do you think the reactivations of cytomegalovirus (CMV), adenovirus, and others are contributing to the really toxic milieu that’s causing this gastrointestinal GVHD?

Robert Zeiser, MD:
You bring up an important point. That’s exactly why these patients have such a high mortality—because they have uncontrolled infections. There were trials with depleting T‑cells with alemtuzumab that are effective at reducing GVHD, but most patients died later due to viral reactivation, adenovirus infections, and fungal infections. Adding more immunosuppression is probably not the key to solving this problem, but rather regenerative approaches, and also, at some point, being courageous and reducing immunosuppression, because here I think healing is the key to success.

Corey Cutler, MD, MPH, FRCPC:
The only thing to add is a push for clinical trials in that setting. We know outcomes are very poor with these patients, so almost all should be enrolled on clinical trials if possible.

Any particular comorbidities in patients with acute GVHD treated with ruxolitinib that we should be concerned about?

Robert Zeiser, MD:
As with all immunosuppressive drugs, there are concerns. You have to monitor viral reactivation, CMV. We do that twice a week in these patients, who are on prophylaxis with letermovir. If the recipient is CMV positive, we do the prophylaxis and we also put these patients on fungal prophylaxis. If patients have low platelet counts, we transfuse them; that is something that can be corrected. And of course, these patients need to be monitored for any kind of infection.

Would patients with severe lung chronic GVHD benefit from ruxolitinib or belumosudil?

Corey Cutler, MD, MPH, FRCPC:
Globally, we haven’t been able to show that individual drugs are better for individual organs.  There doesn’t appear to be tremendous activity for ruxolitinib specifically in lung disease, but there is some rationale for the choice of belumosudil in lung disease, because it is an antifibrotic, and part of the pathobiology of bronchiolitis obliterans is fibroelastosis of the lungs. My colleagues and I in the KD025 (ROCKstar) trials are about to submit a manuscript looking at a combined analysis of the dose‑finding phase Ib KD025-208 and the randomized phase II KD025-213 trials of belumosudil. Results suggest a reasonable response rate in lung disease with belumosudil, on the order of about 1 in 4 patients. These are measurable responses based on FEV1; not simply that the patient felt less short of breath, but they had to have a meaningful improvement in FEV1. So there is some at least anecdotal evidence that belumosudil might be a drug that you might consider for pulmonary GVHD. That being said, it is only approved after failure of 2 or more lines of therapy.

Robert Zeiser, MD:
Ruxolitinib induced a response rate of only 8% in chronic lung GVHD, which is really low. So the question is why? What are we treating here? Is that all from chronic lung GVHD, or have our patients had previous infections of the lung that destroyed lung tissue? Have they had tissue damage due to total body irradiation, which causes fibrosis as well? And therefore, it is a mixed picture, and my impression is that it is very hard to treat chronic lung GVHD. Although I haven’t used belumosudil, in my view, chronic lung GVHD is not responding well to any current treatments, and we need to improve early detection of chronic lung GVHD, to treat it early on rather than when it is established, because it is very difficult to reverse fibrosis and inflammatory destruction of the lung after infections and tissue damage due to conditioning.

Should antithymocyte globulin (ATG) prophylaxis be used in transplant patients?

Robert Zeiser, MD:
In Europe, 2 randomized trials studied ATG prophylaxis in patients undergoing stem cell transplant. A 2009 trial for prophylaxis in the unrelated matched donor setting by Finke and colleagues showed reduced incidence and severity of acute GVHD in patients receiving ATG compared with the control group. Results from a second trial by Kroger and colleagues in 2016 showed in the sibling transplant setting that the incidence of chronic GVHD was reduced in patients who received ATG compared with the control group.

In the United States, however, a trial by Soiffer and colleagues showed that there was actually a decrease of overall survival using ATG, possibly due to different conditioning regimens, with an increased use of total body radiation leading to lower lymphocyte counts. (ATG binds to lymphocytes; essentially it’s an antilymphocyte antibody mixture.) Therefore, it could be that there are higher toxic levels of ATG in those patients, which is one hypothetical explanation for this difference observed in Europe vs the United States.

David Miklos, MD, PhD:
Lymphodepletion is using a fairly blunt tool of depletion of all T‑cells, and a question that is coming out of our CAR T-cell work is, what were the patient’s lymphocyte levels at the start? Research at Memorial Sloan Kettering is focusing on the level of lymphocytes in a patient before conditioning in order to determine the proper dose of ATG. This is a very relevant question, especially when we consider that, as Dr. Zeiser noted, the risk was suggestive, due to increased risks of infection, that lymphocytes of some patients may have been overdepleted. This reminds us that even when you think you have a simple therapy, such as a monoclonal antibody, the dosing, pharmacokinetics, and management across a heterogeneous patient population is really challenging.

How have you changed your GVHD management in response to the COVID-19 risk?

David Miklos, MD, PhD:
I believe right now that administering combination tixagevimab and cilgavimab prophylaxis, which has received an emergency use authorization from the FDA, in patients at high risk due to immune suppression, CAR T-cell therapy, autologous or allogeneic hematopoietic stem-cell transplantation, or ongoing chronic GVHD is very important for these patients. There is a high‑risk feature for our patients who are antibody seronegative for COVID-19, and this is the one therapeutic that we can provide prophylactically that has been supported by the PROVEN study, which showed a decreased risk both of COVID-19 symptoms and of hospitalization and death. And I also want to speak to my colleague Ron Levy’s work that showed, in patients receiving rituximab and other B‑cell–depleting therapies in my CAR T-cell arm of a study at our institution, that getting a patient urgently vaccinated before starting these therapies has shown antibody responses that then demonstrate decreased risks of symptomatic chronic GVHD. 

Get those patients vaccinated before you bring them forward, get the donors vaccinated, and make sure that we’re doing all we can for our patients. And again, if they don’t have antibodies, then let’s get them adoptively transferred antibodies that will give them benefit. 

Your Thoughts?
Which GVHD treatment strategies would you like to know more about? I encourage you to answer the polling question and join the discussion in the comments box below.

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