Dr. Corey Cutler:
Welcome to The ASCO Post Roundtable Series on Treatment Sequencing Considerations for Chronic Graft-vs-Host Disease. I'm Dr. Corey Cutler. I'm the Director of the Stem Cell Transplantation program at the Dana-Farber Cancer Institute and joining me today are two of my colleagues who I'll ask to introduce themselves.
Dr. Betty Hamilton:
Hi, I'm Betty Hamilton. I'm one of the transplant physicians at the Cleveland Clinic, Associate Professor of Medicine of the Lerner College of Medicine of Case Western.
Dr. Hannah Choe:
Hi, I'm Hannah Choe. I'm an Associate Professor at the Ohio State University Comprehensive Cancer Center. I'm the Director of the GVHD program at Ohio State. I'm happy to be here.
Dr. Cutler:
Great, today we'll be discussing recent updates in the treatment of chronic and acute graft-vs-host disease and how we integrate these new developments into a case-based scenario. Our first installment here will focus on first-in-line treatment of acute graft-vs-host disease.
Our first case is of a 56-year-old man who presents with recurrent mantle cell lymphoma after autologous stem cell transplantation. He tried to make CD19 CAR T-cells, but he could not collect enough lymphocytes.
Additionally, he has a prior history of atrial fibrillation and he's currently taking a beta blocker. He's in remission now following second line intensive chemotherapy. The stem cell transplant is recommended and the 9 of 10 unrelated donor is identified. We plan his transplant. The donor prefers a peripheral blood stem cell harvest and peripheral blood stem cells are planned. Reduced-intensity conditioning is offered because the subject had already had myeloablative type conditioning with his autologous stem cell transplant.
For GVHD prevention, the physician plans on using the posttransplant cyclophosphamide regimen with tacrolimus and mycophenolate mofetil. However, because the patient has a history of atrial fibrillation, the investigator decides to reduce the dose of cyclophosphamide to 25 mg/kg/d down from the standard of 50 mg/kg/d. The transplant goes reasonably well. The patient engrafts neutrophils on day 19 and platelets a little later on day 41.
A week following that on day 48 the patient presents with a very classic maculopapular erythematous type rash encompassing about 50% of their body surface area and a bilirubin of 3.1 mg/dL, the direct bilirubin of about 1.8 mg/dL. Without going into real details, we all know that this represents skin stage 3 and liver stage 1 graft-vs-host disease giving this patient grade II GVHD overall. As would be considered standard of care, the patient is started on corticosteroids as first-line therapy for their acute GVHD.
The investigator chooses 2 mg/kg and over the next 7 to 10 days the skin rash gradually fades, improves dramatically. However, the bilirubin continues to rise and peaks at about 6.5 mg/dL. At this point, the investigator 10 days after initiating corticosteroids decides that second line therapy is warranted. We'll get into the discussion portion of this case. I'll start by asking my two colleagues whether the frontline therapy of 2 mg/kg is considered standard in your practice and how you might've done this differently. Betty, let's start with you.
Dr. Hamilton:
I don't know if we might get to this, but I think one of the first things that I might have approached differently is actually the preventative regimen of the posttransplant cyclophosphamide and the fact that it was dose reduced. I think in our field we are often concerned about high doses of cyclophosphamide and cardiotoxicity, but we truly don't understand the full mechanisms of that.
There's a fair amount of retrospective data looking at cardiotoxicity and posttransplant cyclophosphamide with some mixed results. There's also a lot of confounding factors that can contribute to things like fluid overload and atrial fibrillation and arrhythmias and other cardiotoxicity. Potentially, the reduced doses of cyclophosphamide could have increased this patient's risk for graft-vs-host disease.
Getting to your question though in terms of first-line treatment, I think that this is a current standard of care to start with 2 mg, 2 mg/kg of methylprednisolone equivalent for acute graft-vs-host disease. Sometimes in patients who are heavily treated, who are older, we tend to sort of be wary of some high-dose steroids. Given that, still I would say the standard practice is to give high-dose steroids to start.
Dr. Cutler:
I agree both with your assessment of whether we should have reduced dose of cyclophosphamide in this case. Just of note, there are some prospective attempts now to really study reduced-intensity cyclophosphamide. Hannah, now that we are in this situation and the patient has a progressively rising bilirubin, what would you actually do next? Can you tell us a little bit about the evidence behind what you would do?
Dr. Choe:
The only phase III evidence that we have and led to the FDA approval of the only steroid-refractory acute graft-vs-host disease drug we have in our armamentarium is for ruxolitinib on the REACH2 trial. Thankfully, this is now relatively easy to obtain for our patients and a quicker process. Now we actually keep it in stock at my institution and they can start it immediately in a patient as soon as they're admitted. My go-to for someone who is steroid dependent or steroid-refractory for acute graft-vs-host disease is to proceed to ruxolitinib second-line.
I do that begrudgingly because the first thing I would do, and I'm always hesitant to start steroids unless there's a clinical trial available to evaluate either at least an adjunctive therapy in line with steroid-refractory or an alternative first-line therapy in conjunction with steroids. The go-to would be to proceed, especially with anything that is steroid-refractory beyond 7 to 10 days, with ruxolitinib for sure.
Dr. Cutler:
We all certainly would do something very similar and there are a couple of clinical trials that are being done on the national level. Hopefully, we'll hear some results from some of those studies soon, perhaps even as soon as the Tandem meeting in February of '25. Assuming we all would use ruxolitinib in the second-line, Betty, do you want to talk us through some of the results and maybe where we have room for improvement in second-line therapy?
Dr. Hamilton:
Sure, absolutely, as Hannah was saying, the REACH2 trial demonstrated that or led to the FDA approval of ruxolitinib in the steroid-refractory setting. Thus far though, what we know about the durable response of ruxolitinib is still somewhat limited. This trial basically showed that at day 56 only about 40% of patients had a durable overall response, complete responses and partial responses.
There's certainly a lot of room for improvement for drugs that can completely resolve acute graft-vs-host disease and not require reinitiation of therapy or even third-line therapies, which there's obviously not any that are currently FDA approved.
Dr. Cutler:
Not a lot of interest in doing these clinical trials in the third line unfortunately. I think we all believe that the way to improve outcomes in acute GVHD is of course, number one, to prevent more of it and then to use the best drugs that we have in the frontline setting and increase the remission rates and, more importantly, increase the durable remission rates as we know out from the REACH2 studies. Anything about ancillary care of this patient? They're on high-dose steroids. Other things that you think about doing early on to make sure this patient has the best outcome, Hannah?
Dr. Choe:
Early on with high-dose steroids, I think we've also become more cognizant of how toxic steroids are for patients and where our standard was to put patients on a relatively long taper of steroids out of fear that they'll flare even with initiation of second-line therapy. I think we have or at least I have become more comfortable with being a little bit more aggressive about tapering the steroids more quickly upfront once they've proven that they're steroid-refractory.
I also think it's really important to point out that this patient case in particular does have liver involvement and that is increasingly rare to see, particularly in the setting of PTCy now. We see very low rates of grade III through IV acute graft-vs-host disease, which would be the higher stages of lower GI and liver involvement. Liver involvement has become exceedingly rare now with steroid-refractory acute GVHD.
This makes me much more apt to more quickly taper the steroids and move to a next line agent or even with response to ruxolitinib consider what other additional therapies might need to be warming up on the bench for this patient. Tapering the steroids, number one, to limit toxicity, to limit obviously the things that come with high-dose steroids, hypertension, hyperglycemia, poor wound healing, et cetera, and also I think we're learning.
More data is coming out about the direct toxicity of the steroids to our GI tract tissue and to our liver tissue. Number one, certainly removing that, but then also paying very close attention to nutritional status in these patients that have liver involvement as well because that can sometimes be a very limiting factor in terms of treatment, quality of treatment.
Dr. Cutler:
We start proton pump inhibitors early on in these patients and I also think about doing bone health measures early on knowing that these patients might be on corticosteroids for several weeks.
I think we have a couple of key takeaways from this case. Number one, I think we do have to be cautious when deviating from the standard. We now have pretty good evidence that cyclophosphamide at 50 mg/kg is the correct dose until proven otherwise in clinical trials. We know that the durable response rate for steroids upfront is modest, 50% or so. Second-line therapy is often required and the durable response rate there is approximately 40% or so at 2 months. Then, finally, we do have to think about the care of the entire patient, thinking about getting them off steroids early and starting supportive measures; nutrition, bone health, proton pump inhibitors.
This brings us actually to the end of our first case and I'd like to thank Doctors Hamilton and Choe for joining me here. I would encourage you to see the other segments on this case for further discussion about the treatment of chronic graft-vs-host disease or visit ASCOPost.com.
