Risk Factors for Chronic GVHD and Steroid-Refractory Disease


A focused discussion on various risk factors for developing chronic GVHD and steroid-refractory disease.

Case: A 42-Year-Old Woman With Moderate Steroid-Refractory Chronic Graft-Versus-Host Disease

Initial Presentation

  • A 42-year-old woman previously underwent myeloablative conditioning and an allogeneic PBSC transplant for acute myeloid leukemia
  • Received tacrolimus and methotrexate for GVHD prophylaxis
  • At 11 months post-transplant, patient developed moderately dry and painful eyes, mild muscle and joint pain, mild erythematous rash on face and arms

First-line Treatment

  1. Patient received eye drops, topical steroid cream for rash, and was started on oral prednisone at 0.5 mg/kg/day
  2. After 4 weeks of treatment, eye dryness resolved, but the patient’s skin rash and muscle/joint pain worsened; steroid dose was increased to 1 mg/kg/day
  3. Skin rash and muscle/joint pain continued despite increased steroid dose

Second-line Treatment

Patient is now receiving ruxolitinib 10 mg orally twice daily, alongside 1 mg/kg/day steroids

Yi-Bin Chen, MD: Throughout the years, from large registry studies in our own experience, we have clearly identified several clinical risk factors for chronic graft-versus-host disease. The leading one is the past presence of acute graft-versus-host disease; we know that people who've developed acute GVHD certainly have the highest risk to develop chronic, but that's sort of a risk factor as you treat the patient. Prior to transplant, there are several risk factors that are already established, so for patients who receive myeloablative conditioning — specifically those regimens that contain myeloablative doses of total body irradiation, or TBI — we know relative to chemotherapy only or reduced-intensity in non-myeloablative regimens, those patients have a higher risk. Patients who receive a peripheral blood stem cell graft have a higher risk of chronic graft-versus-host disease. Even now in the half-identical setting with post-transplant cyclophosphamide, we know that patients who receive a peripheral blood stem cell graft certainly have a higher risk of chronic GVHD than those who receive a bone marrow graft. Patients who are older and receiving products from donors that are older appear to be at increased risk for chronic graft versus host disease. We also know that male patients who receive grafts from female donors are at risk for more chronic graft-versus-hosts as well.

Still, probably the leading clinical risk factor is HLA [human leukocyte antigen] matching if we use similar platforms. However, we've developed transplant practices where if there are HLA mismatches, we generally use different platforms for transplant than if you have a full match. It's hard to say HLA matched or mismatched is a risk factor for chronic graft-versus-host disease when the platforms differ. If we give more prevention for chronic graft-versus-host disease, and we know how to do that in terms of in the past giving inotuzumab or anti-T-cell antibodies such as ATG [anti-T cell globulin], we were able to decrease the risk for chronic graft-versus-host disease, but we also paid the price in terms of other outcomes such as relapsed infection. The newest, emerging kid on the block is post-transplant cyclophosphamide, and ongoing studies will define if PTSI, as we call it, can reduce the risk of chronic graft-versus-host disease without paying the price in other outcomes.

Steroid-refractory chronic graft-versus-host disease is emerging as a huge unmet need in transplantation. We've improved upon the early mortality and early events after transplantation. We have an increasing number of survivors that are developing chronic graft-versus-host disease, and thus they are refractory chronic-graft-versus host disease. If we look at the percentage of patients in our practice, probably about 35% will develop chronic graft-versus-host disease that requires systemic therapy. Then probably about maybe 50% to 60% of those patients will meet the definition for a second-line agent. Out of the whole population, probably about 20% to 25% while steroid-refractory chronic graft-versus-host disease, in my estimation. Now, steroid-refractory can have several different meanings. It could just be that we start systemic steroids and there is no response and symptoms get worse. It could be that we start steroids and there is a mild response, but it is by no means close to being satisfactory to the patient or myself, and then we have to add something else upon that to improve upon the response. It could also be the steroid-dependent disease where steroids bring about a response, but as we lower steroids to try and avoid the toxicities of such, the symptoms return and so the patients are dependent on a certain dose of steroids, and second-line therapy is added at that point to be able to lower the dose. All 3 of those phenotypes of patients do meet the definition of steroid-refractory in our practice. Are there specific risk factors for developing steroid-refractory chronic graft-versus-host disease? I'm not sure there are beyond the clinical risk factors we already discussed. All of those will have a higher chance of developing steroid-refractory chronic as well, so I don't think of specific risk factors for steroid-refractory chronic outside of the ones that are just there to develop chronic.

Transcript edited for clarity.

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