Treatment Options for Steroid Refractory aGvHD


Yi-Bin Chen, MD, considers potential treatment options for steroid-refractory aGvHD and examines the results of the phase 3 REACH2 study of ruxolitinib.

Yi-Bin Chen, MD: Once this patient was deemed to be steroid refractory, which was obvious in this case, there were a few treatment options. None of them are truly FDA approved, except for ruxolitinib, which was recently approved in 2019. In the past, we used other modalities. These include drugs like sirolimus; mycophenolate; ATG [antithymocyte globulins]; and etanercept, which is the TNF [tumor necrosis factor] blocker. Newer treatments have involved ECP [extracorporeal photopheresis]; a monoclonal antibody called vedolizumab, which targets lymphocyte trafficking and is used for inflammatory bowel disease; and ruxolitinib. Ruxolitinib is the only one that’s been tested in a large phase 3 study, as we’ll discuss. It has the most data to support its use in this setting.

The REACH2 study was pivotal for all in the transplant field, specifically for those of us who do research in graft-versus-host disease [GvHD]. It was a large international phase 3 study that enrolled 294 patients with steroid-refractory acute GvHD and randomized patients in a 1:1 fashion to ruxolitinib 10 mg twice a day vs the treating clinician’s choice of best appropriate therapy. There is a list of options that clinicians could choose from.

The primary end point of this study was overall response rate at day 28, which correlates with long-term outcomes, such as nonrelapse mortality and, more importantly, overall survival.

The key secondary end points were overall survival, overall response rate at other times (eg, day 14, day 56), duration of response, and overall survival.

The authors or investigators need to be applauded for carrying out this trial. Large trials with steroid-refractory acute graft-versus-host disease, much less randomized ones, have been very difficult to do for many reasons. Our patients have many competing risks and toxicities that are hard to judge, adjudicate, and attribute, and they all factor in. This is a huge step going forward in validating the findings of each.

The primary end point of the study, as I said before, was overall response rate at day 28. In the ruxolitinib arm, this was experienced by 62% of patients, with a complete response rate of 34%. In the control arm, this was experienced by 39% of patients, with a complete response rate of about 19%. This was highly statistically significant and validated the experience we were all having using ruxolitinib, as well as the findings of the initial REACH-1 trial and several observational ports.

Other secondary end points showed the durable response at day 56 was higher in the ruxolitinib arm—about 40% compared with 22% in the control arm, thus underlying the durable response that ruxolitinib has in this population—more than helping patients respond the first month and have disease flare.

The findings of this study were important. It’s the first big study in steroid-refractory acute graft-versus-host disease that showed a benefit of one therapy over others. The investments from all investigators merit applause and will help make progress in the field. It was ultimately FDA approved for this indication.

We knew ruxolitinib was a standard of care for steroid-refractory acute graft-versus-host disease, if not the standard of care. There are other agents not yet tested in large trials that many of us have used that brought about clinical responses. It’s not to say that they haven’t had negative results. Many agents have not been tested for a lot of the reasons I talked about in terms of the difficulty in conducting these trials. For the average patient with steroid-refractory acute graft-versus-host disease, ruxolitinib appears to be the standard of care.

There are some clinical factors to take into account. The main toxicity with using ruxolitinib has been cytopenias, specifically anemia and thrombocytopenia, mainly because of its blockade of the signaling cascades of EPO [erythropoietin] and TPO [thyroid peroxidase]. We do see this, but most of these cytopenias can be resolved without dose reductions or transfusions. There are other considerations, too, such as if the GI [gastrointestinal] disease is severe, as well as patients unable to tolerate oral agents. Then, you move to a different therapy, but that is rare in this population.

In our experience using it, we have not had a lot of other adverse events, let alone ones that have caused us to stop ruxolitinib and use another agent. This is not to say that it’s a home run. The overall response rate, while impressive, leaves room for improvement. The durable response rate is less than 50%, so we have more room to figure out what other treatments we can use—for patients who either fail ruxolitinib, or possibly develop assays in predicting which patients will respond to ruxolitinib and which will respond to other therapies.

Transcript edited for clarity.

Case: A 50-Year-Old Woman With Steroid-Refractory Acute Graft Versus Host Disease

Initial Presentation

  • A 50-year-old woman presents on day +32 for a routine follow-up visit after myeloablative matched unrelated donor peripheral blood stem cell transplant for AML.She complains of a new erythematous macular rash and some mildly loose stools which she estimates is 450cc in 24 hours.
  • PMH: unremarkable
  • PE: rash noted on her neck, shoulders, and upper trunk (~60% BSA)

Clinical Work-up

  • Labs: total bilirubin 2.7 mg/dl, AST 60 U/L, ALT 75 U/L
  • Stool testing negative for bacterial/viral infection
  • Negative for HBV, HBV, CMV, EBV, HHV-6
  • Skin biopsy of the rash showed sparse inflammation and abundant dyskeratotic keratinocytes
  • Flexible sigmoidoscopy showed patchy erosion and biopsy showed inflammatory cells with cryptitis
  • She was diagnosed with aGvHD:
    • Skin stage 2
    • GI stage 1
    • Liver stage 1
    • Modified Glucksberg Criteria: grade II; MAGIC Criteria: grade II
  • ECOG 1


  • Admitted as an inpatient for evaluation and initiated methylprednisolone 1.0 mg/kg and topical steroids
  • No treatment response after 3 days, after dose increase of up to 2.0 mg/kg/day IV methylprednisolone
  • After 7 days of systemic steroids diarrhea was around 1500 cc/day, rash was better
  • She was started on ruxolitinib 5 mg PO BID which was tolerated well; increased to 10 mg PO BID 3 days later

Related Videos
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Jamie Koprivnikar, MD, and Hana Safah, MD, experts on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Jamie Koprivnikar, MD, and Hana Safah, MD, experts on MDS
Jamie Koprivnikar, MD, and Hana Safah, MD, experts on MDS
Related Content