Frankfurt Discusses Complications Arising During the Treatment of GVHD

Olga Frankfurt, MD

Olga Frankfurt, MD

During a recentTargeted Oncologylive case-based peer perspectives event, Olga Frankfurt, MD, discussed the complications that could development during the treatment of patients with graft-vs-host disease (GVHD). Frankfurt, an associate professor in the Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, explained these complications in the context of a patient who develops acute GVHD after undergoing hematopoietic cell transplant.

CASE:

A 48-year-old man underwent matched unrelated donor hematopoietic cell transplant with cyclosporine plus methotrexate GVHD prophylaxis. At day 22, he developed Maculopapular rash on his face, upper chest, forearms, shoulders, and upper back with an estimated body surface area involvement of 35%. He also had 4 episodes/day of watery diarrhea for 2 days.

Targeted Oncology™:What are the common GVHD regimens used in clinical practice?

Frankfurt:The standard is either cyclosporin or tacrolimus with either methotrexate or CellCept [mycophenolate mofetil]. There are numerous studies comparing various regi­mens. Definitively, the way that I see it is that a combination of cyclosporin and meth­otrexate is better than single-agent therapy. We can debate whether tacrolimus-based regimens are better than cyclosporin-based regimens and so on. A lot of people like to use sirolimus-based regimens. We typically use tacrolimus with methotrexate or, if we don’t use methotrexate, then we use mycophenolate mofetil and tacrolimus. 

It is rare that I skip the 4 doses. The mucositis has to be so severe that I would be afraid to intubate [the patient]. In that case, I might skip the last dose, but usually I try not to do it because the data suggest that you need 4 doses; otherwise, you will be dealing with GVHD.

What percentage of patients develop acute GVHD (aGVHD)?

The answer is always &ldquo;it depends.&rdquo; It is close to 50%. Some studies will say <30%, some will say >60%, but the answer is that a significant proportion of patients will develop GVHD.

Should biopsy be performed to confirm GVHD?

I usually do it if I can. Imagine that this patient does not have diarrhea; this could be an antibiotic-related reaction, especially if it&rsquo;s not the most classic presentation. Typically, I would ask for a skin biopsy.

Would you use antithymocyte globulin (ATG) for this patient?

The only reason we would use ATG is [in the case of] aplastic anemia. Typically, we would not use an ATG-based regimen because of the risk of infections and relapse.

What about the use of Cytoxan (cyclophosphamide)?

Everybody is loving [cyclophosphamide]. The reason we can do so many haploidentical stem cell transplants [haplo-SCTs] now is because the posttransplant cyclophosphamide seems to lead to great control of GVHD, and it does not appear to increase the risk of relapse. From what I understand, some are beginning to use it for regular transplant, not just haplo-SCT. I use it in the case of haplo-SCT and in clinical trials, but not during routine treatment.

Can you offer a brief overview of the cellular mechanisms that lead to GVHD?

In general terms, the conditioning regimen of chemoradiation leads to tissue damage, which leads to endogenous and exoge&shy;nous production of molecules necessary for immune function. That leads to, among other things, the expression of MHC [major histocompatibility complex] antigens and other molecules, which costimulate the production of the donor T cells [and a subsequent reaction] with the initial recipient&rsquo;s antigen-presenting cells early in the course of GVHD. Later, donor cells stimulate the circular cascade, and that creates a generation of immune T cells, with the endpoint being the infiltration of the recipient&rsquo;s organ tissue. Following that are all the terrible consequences of aGVHD.

The risk factors for aGVHD have been known for a long time. The degree of match [with the donor] is the most crucial factor contributing to GVHD. For patient age, we prefer younger donors and patients. I know many of my colleagues in large transplant centers would use an older donor, but we do not. If I have a 20-year-old [donor], I will take them over the 63-year-old sibling. We would particularly like to avoid sex mismatch if we can. The intensity of the preparative regimen is directly related to the development of GVHD, particularly high-dose, whole-body radiation.

Discuss the importance of the Mount Sinai Acute GVHD International Consortium (MAGIC) organ staging system.

This is what is present on each [clinician&rsquo;s] desk, because we have to record the staging of the GVHD. [There are symptom categories for] the skin, liver, upper gastrointestinal [GI], and lower GI systems. Our patient with his 35% body surface area rash would be stage 2 skin GVHD and stage 1 GI GVHD (TABLE 1).¹The overall clinical grading involves putting them all together for a clinical trial, documentation, and communica&shy;tion purposes (TABLE 2).¹

How much steroid should be given to this patient?

There is big debate about this, as well. Typically, we would do 1 to 2 mg/kg of prednisone equivalent. There are multiple trials trying to compare various doses of steroids, and it does not appear to be advantageous [to increase the dose].

CASE (continued):

The patient received prednisone 2 mg/kg per day for 14 days. Skin rash was reduced to grade 1 and diarrhea resolved.

The steroid dose was then tapered by 0.2 mg/kg per day every 3 days. At 1.2 mg/kg per day, he reported the spread of the skin rash and 2 loose bowel movements per day.

What are the management options for this patient?

We do not have a specific taper regimen; it depends on how much the patient responded and how much you are worried about the steroids. Here, they used a specific algorithm, and they tapered by 0.2 mg/kg intervals. That is not unreasonable.

As you get down to the lower doses, you notice an increase in skin rash and bowel movements. They key thing is sometimes you cannot tell things apart. Patients after transplant are compli&shy;cated. They could have CMV [cytomegalovirus], they could haveC diff[Clostridioides difficile], drug reactions, or many other reasons that would cause rash, diarrhea, or both. It is important at this point to make sure you are still dealing with the same GVHD. If you are confident that this is GVHD, figure out what to do.

How and when is steroid-dependent versus steroid-refractory GVHD defined? What are the triggers to escalate/change the management approach?

If you have a progression of aGVHD within 3 to 5 days of onset of treatment of a hefty dose of steroids, or if the treatment has been going on for 5 to 7 days and there is no improvement, then you need to start thinking about what else there is to do. It can be complicated, because on one hand, you want to taper steroids, but on the other, you are afraid. That is part of the sequence.

Steroid dependence is when you are not able to taper steroids. Every time you go below a specific dose, the patient flares up and you have no choice but to increase the steroid doses. Steroid intolerance can happen in fragile diabetics, and they can develop osteonecrosis of the joints. Giving steroids [to these patients] becomes a problem (TABLE 3).²

What are the treatment options for this patient at this point?

Ruxolitinib [Jakafi] has received an FDA approval for aGVHD, so it now is the drug that we all go to for the management of GVHD.³The results from phase II REACH-1 study led to the approval of this drug. It was intended for grade 2 to 4 aGVHD. Eligible patients were allowed to enroll after 3 days if they progressed on up to 3 days of high-dose methylprednisolone or had no response after 7 days of treatment. Interestingly, they included patients age 12 and above, which is great. There had to have&nbsp;

been some evidence of myeloid engraftment and some standard criteria: no evidence of organ failure, uncontrolled infections, etc.

The primary endpoint was overall response rate [ORR] at day 28, and there were secondary endpoints such as overall response, incidence of chronic GVHD, nonrelapse mortality [NRM], safety, and [rate of] discontinuation.⁴

The ORR [overall response rate] at day 28 was 54.9%, with complete remission in 26.8%. Best ORR during treatment at any time was 73.2%. The median time to response was 7 days [range, 6-49 days]. This is quite unusual because with ECP [extracorpo&shy;real photopheresis], you are waiting for a long time to see some improvement, but it is remarkable when you start treatment and, in a few days, patients are saying they feel better.⁴

The median duration of response in those who responded was 345 days. The rate of relapse was 5.6%, and that is an impor&shy;tant point. Preclinical data showed GVHD effect was noticeable; there was no decrease in graft-vs-leukemia effect. Hopefully, this drug does not lead to increase of relapse of underlying disease.⁴

NRM at 6 months is still good at 44.4%. Median overall survival for day 28 responders had not been reached. At the follow-up, just 11 patients out of 71 were ongoing.⁴

What are the toxicities associated with this agent?

The JAK1 inhibitors typically inhibit the macrophage function, and it does increase risk of infections. The adverse events observed in REACH-1 are not particularly above what you would see in aGVHD. There were 2 mortality events, 1 sepsis and 1 pulmo&shy;nary hemorrhage.

Are other trials examining ruxolitinib in this patient population?

The phase III REACH-2 trial [NCT02435433] is randomizing patients to receive either steroids with ruxolitinib 10 mg twice daily or standard-of-care steroids with CNI [calcineurin inhibitor]. Patients who are on ruxolitinib who do not respond have to come off the study. Patients who do not respond on the standard arm are able to cross over after 6 cycles.

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. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position state&shy;ment on standardized terminology & guidance for graft-versus-host disease assessment.Bone Marrow Transplant. 2018;53(11):1401-1415. doi: 10.1038/s41409-018-0204-7.
3. FDA approves ruxolitinib for acute-graft-versus-host disease. FDA website. fda.gov/ drugs/resources-information-approved-drugs/fda-approves-ruxolitinib-acute-graft-versus-host-disease. Published May 24, 2019. Accessed September 29, 2019.
4. Jagasia M, Ali H, Schroeder MA, et al. Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease: results from the phase 2 REACH1 trial.Biol Blood Marrow Transplant.2019;25(3):S52. doi: 10.1016/j. bbmt.2018.12.130.