Bishop Reviews Risk Assessment and Treatment for GVHD

A recent Targeted Oncology case-based roundtable event was lead by Michael R. Bishop, MD, professor of Medicine, and director, David and Etta Jonas Center for Cellular Therapy at the University of Chicago in Chicago, IL. During the event, Bishop discussed a patient with graft-versus-host disease who underwent a myeloablative conditioning regimen and peripheral blood stem-cell matched hematopoietic cell transplant.

Michael R. Bishop, MD

Targeted Oncology^TM: What should oncologists know about GVHD?

BISHOP: GVHD is a leading cause of nonrelapse mortality [NRM] following allogeneic stem cell transplant. The No. 1 cause of mortality is, unfortunately, relapse. We now see both acute and chronic GVHD as probably the second leading cause of death and the No. 1 cause of NRM.

Acute GVHD is a reaction of donor immune cells, primarily from the graft, that affect the following 3 tissues in the recipient: skin, liver, and gastrointestinal [GI] tract. Chronic GVHD is a syndrome that has a lot of similarities to autoimmune diseases seen outside the transplant realm. It may involve a single organ or multiple organs. Biologically, [it occurs from] T cells and B cells that arise from the stem cell graft from the bone marrow after engraftment has occurred.

The risk factors for acute and chronic GVHD are very similar. Acute GVHD was considered the greatest risk factor for chronic GVHD, but that’s not necessarily true due to the different ways that we’re doing transplants now, as opposed to the classical way they were done prior to the turn of the century.

With standard GVHD prophylaxis, approximately 25% to 50% of patients who receive a human leukocyte antigen [HLA]-matched stem cell graft will develop GVHD that requires high-dose systemic steroids. Unfortunately, approximately 50% of these patients will have an inadequate response, meaning either a lack of response to treatment or an inability to get off steroids once they achieve a response.

GVHD develops in 3 phases as was described by the work of James L. Ferrara, MD, who has been a leader in our understanding of the biology of acute GVHD. The first phase occurs due to tissue damage from the conditioning regimen leading to an inflammatory response that releases cytokines such as IL-6 and tumor necrosis factor [TNF], and damage within the small intestine leads to release of lipopolysaccharides.¹

These inflammatory cytokines stimulate host antigen-presenting cells [APCs], and those donor T cells that are within the graft see these host antigens presented by the professional APCs and become activated. This leads to the development of type 1 helper T cells, which release inflammatory cytokines such as interferon-γ and IL-2. Concurrently, the lipopolysaccharides get taken up by macrophages, which can lead to further stimulation of T cells. Eventually, the target antigen—be it on skin, the intestinal tract, or the liver—is attacked by these activated cells. All 3 phases are necessary for the activation of acute GVHD.

Our first goal is to prevent GVHD, and there are several ways to go about it. Probably the most traditional way is using calcineurin inhibitors, such as cyclosporine and tacrolimus [Prograf], in combination with methotrexate. Calcineurin inhibitors can also be combined with mycophenolate mofetil and with sirolimus [Rapamune]. Sometimes, a combination of 3 medications is used.

For a long time, people have also used T-cell monoclonal antibodies. Antithymocyte globulin [ATG (Thymoglobulin)] is commonly used, particularly in unrelated donor transplants. But there are also data, particularly from the United Kingdom, on the use of alemtuzumab [Lemtrada] to deplete T cells in vivo.

We can also do ex vivo T-cell depletion by doing CD34 selection in the graft, where the T cells are removed and CD34 cells are maintained. T-cell depletion has long been used to prevent GVHD. A more interesting and back-to-the-past type of treatment is the use of posttransplant cyclophosphamide, which was based upon early work done by George W. Santos, MD, at Johns Hopkins University in the 1970s.

It has been further developed more recently by the Johns Hopkins group to permit the transplantation of haploidentical grafts and is being applied to unrelated donors in HLA-matched sibling grafts with a high degree of success. The problem is, once GVHD develops, there can be difficulties in trying to control it with steroids alone. There are several potential targets that one can use to try to control it. There are calcineurin inhibitors such as tacrolimus, cyclosporine, and sirolimus. There are ways to block the T-cell receptor, such as by using ATG. TNF is one of the cytokines that gets activated, and we can think about etanercept [Enbrel] or infliximab [Remicade] to block it. Another T-cell–expressed antigen is CD52, blocked by alemtuzumab.²

For other inflammatory cytokines that get activated during the second phase of GVHD activation, we can look for antibodies that block IL-6 receptors, such as tocilizumab [Actemra], and IL-2 receptors, such as daclizumab [Zinbryta] and basiliximab [Simulect]. Researchers have looked at blocking the cholesterol pathway through atorvastatin [Lipitor], CASP3 blockade, and bortezomib [Velcade] for the proteasome pathway. There is also rituximab [Rituxan] because B cells can be an APC, as well. So, we have several molecules and every one of these has been investigated, either primarily for the treatment of GVHD [or] in some cases the prevention of GVHD.²

What are the risk factors for acute GVHD?

Donor recipient factors include class I and class II major HLA disparity. Looking at minor HLA disparity is not something we commonly do. Then there is sex matching, donor parity, and donor age. For ABO mismatch, there is a slight increase in risk of GVHD but not a big deal. Donor CMV serostatus is a very big deal. But sometimes we will select a CMV-positive donor in the situation where the recipient is also positive. [Individuals] have looked at cytokine gene polymorphisms, but that’s not a common practice in our clinical situation.

For [stem cell graft factors], there is the stem cell source, for example if it is peripheral blood vs bone marrow vs umbilical cord blood. But there are data that make this controversial. For stem cell graft composition, if T cells are depleted, the incidence of GVHD is very low. Researchers haven’t been able to quantitate the perfect T-cell dose.

There are some controversial data about very high CD34 dose, but this is generally when you get to 10 × 107 CD34/kg cell dose that you start seeing this higher incidence of GVHD. For [conditioning intensity], there is a myeloablative vs a reduced-intensity condition regimen.

What stage/grade GVHD does this patient have? Are there institutional preferences for grading/staging for acute GVHD?

Based on the Mount Sinai Acute GVHD International Consortium [MAGIC] criteria [for organ staging of acute GVHD], this patient, because he had 60% [body surface area involvement], would be put at stage III. The other important thing is how many diarrhea episodes the patient is having. I don’t know how it is at other institutions but getting the nurses to accurately measure [diarrhea volume] has been tough for us. But in an adult, it would be stage I for up to 4 diarrhea episodes a day. When you can’t do an absolute volume measurement, then you can go by the frequency of the episodes. When we take it all together, this patient had stage III rash, and he had stage I lower GI involvement. He would have an overall grade 2, based upon the MAGIC criteria.³

So, [the overall clinical] grade would be 2 at a minimum, but it was an unfair question because they didn’t give us all the information needed. There was the University of Minnesota acute GVHD stratification, which Margaret MacMillan, MD, MSc, had written about as early as 2012.⁴ But what was more important was its multi-institutional confirmation that was published in 2015. They were able to demonstrate that they could divide GVHD into standard risk vs high risk. Now, fortunately, the high-risk individuals were a small proportion, but it was defined as any involvement of 1 organ with stage IV for the skin, stage III to IV for the gut, and stage I to IV for the liver.⁵

The reason that [risk stratification] is important is that it correlates with a probability of treatment-related mortality [TRM]. The multi-institutional verification of the [University of Minnesota] stratification plan demonstrated about a doubling in terms of TRM in the high-risk vs standard-risk groups.⁵

A paper published by John E. Levine, MD, and his colleagues from the University of Michigan looked at a combination of different molecular markers and cytokines, and were able to demonstrate that, based upon this, they could stratify patients into high-risk and low-risk GVHD.⁶ They looked at these markers during the early onset of the disease. Some researchers have tried to look at this before the disease onset. There is a modified version where they use [TNF], ST2, and REG3, and it seems to correlate well with the Levine et al version in terms of overall survival [OS] and particularly TRM.

What data support the use of ruxolitinib (Jakafi) alongside steroids in steroid-refractory GVHD?

The REACH1 study [NCT02953678] was a [phase 2 trial for patients with steroid-refractory acute GVHD]. They started with ruxolitinib at 5 mg twice a day and maintained steroids. On day 4, if their counts, particularly platelets, were looking fine, they could go straight to 10 mg twice daily. The overall response rate [ORR] was the primary end point.⁷

The ORR at day 28 was 55%, and the best ORR at any one time was 73%. It was encouraging that the response was generally seen within a week, as early as day 6. The median duration of response [DOR] among responding patients was approximately 11 months. The NRM at 6 months was 44% and the median OS had not been reached.⁸

This led to the phase 3 REACH2 study [NCT02913261], which was primarily a European study, that had patients with steroid-refractory acute GVHD. What differed from REACH1 is that they started ruxolitinib at 10 mg twice daily. They had a best available therapy [BAT] control arm, chosen by the investigator. It was published in the New England Journal of Medicine by Zeiser et al.⁹

The BAT included ATG, extracorporeal photopheresis [ECP], mesenchymal stem cells, low-dose methotrexate, mycophenolate mofetil, everolimus [Afinitor], sirolimus, etanercept, or infliximab. The most common investigator choice of BAT was in the supplement, and it was ECP, which is interesting. Patients had the ability to cross over, and again the primary end point was ORR at day 28. The key secondary end point was durable ORR at day 56.

The ORR at day 28 was 62% for ruxolitinib vs approximately 40% for investigator-choice BAT [odds ratio (OR), 2.64; 95% CI, 1.65-4.22; P < .001 (Figure9)]. The complete response rate for ruxolitinib was almost double that of BAT [at 34% vs 19%, respectively]. The secondary end point of durable ORR at day 56 was 40% for ruxolitinib vs 22% for BAT [OR, 2.38; 95% CI, 1.43-3.94; P < .001]. For the full analysis, they broke it down by grade. Across all grades, even in grade 4 disease, there was an advantage for ruxolitinib. There was an improvement in patients with liver involvement too.

For the DOR, an overwhelming majority of patients in the ruxolitinib arm were compared with those in the control arm. The DOR maintained superiority in the ruxolitinib arm. For significant improvement in staging of the skin, upper GI, lower GI, and liver, ruxolitinib was superior.

The failure-free survival [FFS] was also superior for the ruxolitinib arm. [It was 5 months for ruxolitinib vs 1 month for BAT (HR, 0.46; 95% CI, 0.35-0.60)]. It didn’t quite reach statistical significance but still improved FFS in the ruxolitinib arm.

It is important to know that the relapse was not any higher [for the ruxolitinib arm]. For toxicities, the incidence of thrombocytopenia nearly doubled for [ruxolitinib at 33% vs 18% for the BAT control arm], and that’s not a big surprise. With ruxolitinib, you’d need to monitor [platelet count]. There was a slightly higher incidence of [CMV] infection and I think infections overall with ruxolitinib.

_REFERENCES

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_{3. 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}

_{4. MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol. 2012;157(6):732-741. doi:10.1111/j.1365-2141.2012.09114.x}

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_{7. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, von Bubnoff N. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10(5):391-402. doi:10.2217/imt-2017-0156}

_{8. 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}

_{9. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635}