Ruxolitinib Displays Durable Responses in Patients With Acute Graft-vs-Host Disease

Michael R. Bishop, MD

During a Targeted Oncology Case-Based Roundtable event, Michael R. Bishop, MD, professor of Medicine and director, Hematopoietic Stem Cell Transplantation Program in the David and Etta Jonas Center for Cellular Therapy ay The University of Chicago Medicine, discussed the case of a 48-year-old- male patient with acute graft-versus-host disease.

Targeted Oncology^TM: What is the patient’s risk for developing acute GVHD?

BISHOP: We know that if the recipient was CMV positive, using a CMV-positive donor may be beneficial because there can be some passive immunity toward preventing CMV reactivation. But the risk still increases for acute GVHD, and if the recipient was CMV negative, that would be worse. In those situations, if you have a CMV-negative recipient, we always want to use a CMV-negative donor, if possible.

How do the 3 pregnancies that the donor had affect the risk of developing GVHD?

With every pregnancy, the risk of GVHD goes up. If you look at women who are supposedly nulliparous, if you look at that compared with a male donor, the risk is higher. That’s probably because a certain percentage of women may have [been pregnant and not known], because we know that there’s a 20% to 30% incidence of spontaneous abortions. For [those women], it’s probably that antigen exposure from the male donor [that] leads to GVHD.

How does the graft source factor into this?

The graft source was a matched unrelated donor, but we didn’t know if [the patient received] peripheral blood or bone marrow. There’s some indication that peripheral blood may have a higher incidence of acute GVHD. We’re also assuming that this was a T-cell replete graft; they didn’t do any form of ex vivo T-cell depletion, they just said they [used] an unrelated donor. Then the patient received methotrexate and a calcineurin inhibitor, so we would assume it was a T-cell replete. If there are T cells within the allograft, that increases the risk of GVHD.

What other risk factors should be considered?

Of the conditions that increase the risk of GVHD, human leukocyte antigen mismatched donor [factors higher than] a matched donor, [but] our patient had a matched donor. An unrelated donor [also factors higher than] a related donor, and our patient had an unrelated donor. In the sex matching, male is always higher.

One thing [I] didn’t mention was ABO [blood type] mismatch. I never think of that as a major contributor to GVHD, but there [are] some data [that show this]....An ABO mismatch lightly contributes [to the risk of developing GVHD], but ABO would probably be the lowest on that [scale]. There are some [individuals] who look at gene polymorphisms, but I don’t think we have the selectivity. If we had everything else matched, looking at cytokine gene polymorphisms would be important.

When we look at stem cell source, peripheral blood [increases risk more than] bone marrow, [which increases risk more than] cord blood, in terms of risk of GVHD. Higher CD34 count [increases risk, as well], but you have to get really high, on the order of 10 million cells per kilogram to get a higher T-cell dose. Although with the lower T-cell dose, if you just take the T cells out, once you get to a certain point of T cells, giving more is not going to be worse.

How would you prioritize the next step for this patient?

If I saw this patient and the diarrhea was minimal, I could recommend giving some Imodium, getting stool cultures, and starting topical steroids. [I would also get] a biopsy to confirm GVHD, because the skin [rash] and everything else could be due to a few other things. [Testing] for acute biomarkers is a great answer if you have it at your institution because it gives you a helpful view in terms of diagnosis and prognosis. It sounds [as though] he’s in a time frame—it’s a little early at day 22, median onset is usually around 4 to 5 weeks, and here it’s [approximately] 3 weeks—but it sounds pretty close to acute GVHD, so I wouldn’t fault any of these answers.

What are the different staging systems for GVHD?

Mount Sinai Acute GVHD International Consortium [MAGIC] added a new element, and it’s this upper GI [gastrointestinal] section.1 We know that [approximately] 30% of patients can have onset of anorexia or nausea. Some people even think that the upper GI has a worse prognosis than that of lower GI. So, this has been added in MAGIC to the new grading scale, and it adds a new factor when you’re evaluating patients for acute GVHD.

The overall [MAGIC] grading system is based upon the [general] stages of disease, from [no stage of any organ to stage IV on the skin, liver, lower GI involvement, with stage 0 or I upper GI].

What is the importance of risk stratification in the treatment of this patient population?

One of the biggest things that comes up with the [Center for International Blood and Marrow Transplant Research] is whether a patient is at standard risk or high risk. They put this classification in because organ involvement and stages can make a big difference. [The difference is] whether there’s 1 organ, 2 organs, or 3 organs [affected], and then what the various stages of disease they are at.2 So, you can still have a single organ, but if you have stage IV of the skin or stage III of the gut [or] any stages of the liver, that puts the patient into a higher-risk category....[Also], hepatic involvement is generally associated with a higher risk.

For patients [considered to have] standard risk, the overall response rate [ORR] was [approximately] 70%, but if you add in the high-risk category, it drops down to a little over 40%. The probability of getting a complete response [CR] is better in [patients who are] standard risk than higher risk, but what’s important is treatment-related mortalities. So, if a patient has high-risk acute GVHD, the treatment-related mortality was [approximately] 45%, as opposed to between 20% to 25% in the standard-risk category. This has been valuable, too, in trying to think about ways of treating GVHD and designing subsequent clinical trials to address it.

Some cytokines [and biomarkers have] independently been demonstrated to be associated with acute GVHD.³ Patients gave multiple samples starting at 2 weeks, [then] 4 weeks, 6 weeks, 8 weeks, going out for a year, and what [the investigators] did is put together a panel. If patients had an association with 1 of these cytokines, if they had low levels, it predicted a better outcome, in terms of both GVHD and overall survival [OS].

What are the guidelines for a patient such as this?

With NCCN [National Comprehensive Cancer Network] guidelines for both acute and chronic GVHD, [a number of agents] could target the disease biologically, based upon receptor and pathways within T cells and in the [GVHD] cells.4 However, the problem is, we only have 2 drugs that are FDA approved [for] acute GVHD— ruxolitinib [Jakafi] and ibrutinib [Imbruvica]—although I think we may get another indication for ruxolitinib in chronic GVHD soon.

Please discuss the design and efficacy of the REACH-1 (NCT02953678) study.

The REACH-1 study was what led to the approval of ruxolitinib for acute GVHD. This phase 2 trial was primarily done in the United States for patients with steroid-refractory GVHD.⁵ All the patients had to have been on 2 mg/kg of a steroid, or equivalent, and not received anything else. There were 71 patients enrolled on this trial, but the problem is that 29 of them were found to be ineligible for treatment. So, when you read about the results, it’s only [from] 42 patients, because half of the [ineligible] patients had been on more than 1 agent, and the other half hadn’t been on an adequate amount of steroid.

[The outcomes of the trial] showed that the ORR was nearly 55%, and approximately 25% [of patients] achieved a CR.⁶ The best ORR, if they continued treatment, was at day 28, which was the primary end point. Nearly half the patients achieved a CR, and three-quarters of the patients had an ORR [73.2%]. The neat aspect of this drug is that the median time to response is 7 days. It’s very rare to see late responders, but generally, [approximately] 80% to 90% of patients we start on ruxolitinib, if we’re going to see a response, [will have it] within the first 4 weeks. If you look at the median duration of response... it was nearly 11 months. And death, [caused by something] other than malignancy relapse, was seen in 49% [of patients, which is] still not great; non-relapse mortality [was] 44%, and median OS at 28 days wasn’t reached.

Are there other randomized data supporting the use of ruxolitinib in these patients?

The REACH-2 study [NCT02913261] was a randomized phase 3 study looking at patients [with identical criteria to REACH-1], and there were 294 patients enrolled.⁵ So, 294 patients were randomized; [however], patients on REACH-1 started at ruxolitinib 5 mg twice a day and then went up, but these patients automatically started at 10 mg. Half the patients were randomized to physician’s choice in terms of how they could treat the GVHD. They assessed the response at day 28; on the control arm, if they weren’t responding, they could cross over and receive ruxolitinib.

What were the results of REACH-2?

The ORR with ruxolitinib was 62% compared with the control arm at 39%.7 The majority of the responses on ruxolitinib were CRs, and the responses tended to be durable [Investigators also] looked at ORR at day 56, and 40% of the patients were still maintaining a response. The majority of those were CRs compared with only 22% on the control arm.

When the investigators looked at it based upon the full subset of patients, there was an advantage for ruxolitinib versus the best available therapy. When you look at ruxolitinib in the steroid-refractory population, the ORR was 20% versus 13% in the best available arm, and the hazard ratio, in terms of improvement, was 3.76 [95% CI, 1.24-11.38]. So, this worked in all subsets of patients.

Before patients would relapse, if they had a response on ruxolitinib, only 10% of patients lost that response compared with 40% of patients who responded on the best available treatment arm. When [the investigators] restaged the disease, they looked at it by skin, liver, upper GI, and lower GI, and there was more significant improvement in terms of stage. Downstaging was better in every single organ relative to ruxolitinib.

Were there any adverse events from the use of ruxolitinib to consider?

The only bad thing is that ruxolitinib causes a high degree of myelosuppression. There was an increased risk of infections in both arms [of the REACH-2 trial]. The overall toxicities were still high on both arms because these are all steroid-refractory patients, but there was a higher degree of thrombocytopenia. Moreover, 33% [of patients, which is] a significant proportion, had grade 3 GVHD, grade 3 thrombocytopenia, and CMV infections.

_References:

_{1. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j. bbmt.2015.09.001}

_{2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001}

_{3. Levine JE, Logan BR, Wu J, et al. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012;119(16):3854-3860. doi:10.1182/blood-2012-01-403063}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation, version 2.2021. Accessed April 23, 2021. https://bit.ly/3ocIjNV}

_{5. Jagasia M, Zeiser R, Arbushites M, et al. Ruxolitinib for the treatment of patients with steroidrefractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10(5):391-402. doi:10.2217/imt-2017-0156}

_{6. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823}

_{7. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graftversus- host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635}