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Graft-vs-Host Disease Management in the Modern Era: Expert Insights on Incorporating Recent Advances Into Care

Corey Cutler, MD, MPH, FRCPC
Released: April 13, 2020

Graft-vs-Host Disease Management

What Is GVHD?

What is GVHD? GVHD, in its simplest form, is when immune cells from the donor attack host tissue in the recipient. GVHD is similar to rejection of a solid organ transplant such as a kidney, where the immune system tries to reject the kidney. However, in GVHD, the immune system is the transplanted organ and it tries to reject the host tissues.

aGVHD occurs in 30% to 60% of patients who undergo transplant, but there is a positive aspect. The graph on the slide shows the posttransplant probability of relapse over time, and as seen with the lower curves, having a degree of GVHD may decrease the likelihood of posttransplant relapse.[1,2]

Individuals who have T-cells removed from the graft or who are identical twins and, therefore, not really receiving a true allogeneic transplant, have the lowest rates of GVHD, and those individuals have the highest rate of disease relapse. Individuals who get some amount of GVHD and who have allogeneic reactivity are those who have the lowest rate of leukemia relapse. This suggests that the donor graft is not only recognizing normal host tissues as foreign but also recognizing the leukemia cells and other malignant tissues as abnormal as well.

GVHD Syndrome After AlloHCT

There are 2 main types of GVHD, as shown on this post–allogeneic hematopoietic cell transplantation (HCT) timeline. We have the first curve of aGVHD, which generally occurs within the first 100 days after transplant, and then the second wave of GVHD, called cGVHD, which generally occurs after 100 days from transplant. However, these 2 diseases are not defined strictly by their time from transplantation, because there is late aGVHD and early cGVHD, and you can even have patients who have both syndromes occurring simultaneously, which is called overlap syndrome.

GVHD Pathology: Acute and Chronic GVHD

GVHD is pathophysiologically complicated. aGVHD is thought to be mediated almost entirely by mature alloreactive T-cells, which recruit other immune effectors to the site of immunologic attack. cGVHD is more complicated, involving cells of several other lineages, including B-cells and cells of the monocyte-macrophage lineage, and it is a far more difficult process to define immunologically.[3]

3-Step Cytokine aGVHD Model

aGVHD has been thought of as a single, linear process. Inflammation and tissue damage from conditioning injury or other signals of inflammation in the host lead to an expansion of activated T-cells. These T-cells express various cytokines, most notably IL-2, which upregulates and draws more T-cells into the tissue, which in turn activate local neutrophils to cause tissue injury.

aGVHD affects 3 organs only: the skin, where it presents with a rash; the gastrointestinal (GI) tract, where it presents predominantly with watery diarrhea; and the liver, where it presents predominantly with hyperbilirubinemia.[4]

Acute GVHD: Staging by MAGIC Criteria

The most commonly used system for the staging and grading of aGVHD is the modified Glucksberg or modified consensus criteria. The Mount Sinai Acute GVHD International Consortium (MAGIC) modified the criteria, and the MAGIC criteria are shown in this table. [5] Individual organ stages are always numbered using Arabic numerals (1, 2, 3, 4) and each individual organ is given its own stage. The skin is staged based on the degree of rash, the liver is staged based on the degree of hyperbilirubinemia, and the GI tract is staged based on the volume of diarrhea or the number of episodes per day. Upper GI GVHD can also be staged.

The individual organ stages are added together for an overall grade of GVHD. The overall grade is enumerated using Roman numerals rather than Arabic numerals and it is a composite score taking into account the maximum stage of aGVHD of the individual organs.

3 Biologic Phases of cGVHD

cGVHD is somewhat more complex. The pathobiology of cGVHD is divided into 3 biologic phases. [6] Phase 1 includes problems with innate immunity. Phase 2 is the upregulation of the immunologic effect related to allogeneic immunity, in which the patient has chronic inflammation and dysregulation of the immune system. It is during phase 2 that researchers believe that B-cells might be more active; there is certainly a role for the regulatory cells in this phase. In phase 3, once there is symptomatically active cGVHD, scarring and fibrosis are prevalent.

Chronic GVHD Assessment

cGVHD may involve many more organs than in aGVHD, as shown on this slide, with many additional complications; therefore, cGVHD is staged and graded in its own fashion. Each organ that may be involved in cGVHD is given an organ severity score from 1-3. All of the individual organ scores are put into a composite National Institutes of Health overall category of cGVHD: mild, moderate, and severe, with severe indicating a disability in at least 1 organ system. For example, an individual who has moderate to severe lung disease affected by GVHD is automatically considered to have severe cGVHD.

Targeting T-Cell Signaling Pathways

Let’s talk about emerging therapeutic targets in GVHD. This schematic shows the 3 signals and the pathways believed to be involved in upregulation of T-cell responses.[7] Signal 1 involves the presentation of peptide/MHC complexes on the antigen-presenting cells to the T-cell receptor on the T-cell. A costimulatory signal, or signal 2, is required along with signal 1 and is provided by stimulation of CD28 on T-cells by CD80/86 on antigen-presenting cells. Cytokine signaling is considered to be signal 3 in the immune synapse. The combination of 3 signals gives us several steps where we can intervene in terms of prevention or treatment of GVHD.

Targeting Signal 1: Antigen Presentation

Signal 1 is antigen presentation and ligation of the T-cell receptor. How can we block this step? Without T-cells this step doesn’t happen, so the easiest and most obvious way of doing this is with T-cell depletion, which can either be done using pharmacologic agents, such as antithymocyte globulin (ATG) and alemtuzumab (anti-CD52), or by killing off T-cells using cyclophosphamide early in the posttransplant setting. The other way to do this is to manipulate the graft by depletion of T-cells—either all of them or specific populations such as the naive T-cells or the alpha-beta T-cell receptor–positive cells. Another strategy involves removing the T-cells from the graft, transducing the T-cells with a suicide gene construct, and then killing these cells off using an exogenous signal in the event of GVHD.

Targeting Signal 2: Costimulation

We have also taken advantage of signal 2, which is the costimulatory signal for GVHD prevention. The graphic shows costimulation occurring via CD28 with CD80/86 on the antigen presentation cell. Blocking antibodies can be used against this interaction and the one that is most commonly used is abatacept, a CTLA-4 immunoglobulin inhibitor.

Targeting Signal 3: Cytokine signals

Signal 3 is related to cytokine signaling. Shown in this table are receptors for several of the important cytokines believed to be associated with GVHD signaling. The signal transduction for various cytokines is through the JAK/STAT pathway, with different cytokine receptors utilizing different JAK pathways. Current approved drugs and experimental compounds that are known to affect the individual JAK signaling pathways are listed under the corresponding receptors.[8]

B-Cells in Chronic GVHD

While a B-cell can interact with a variety of T-cells, B-cell/T-cell interactions are not considered important in the aGHVD setting. They are important, however, in cGVHD. The B-cell receptor can be targeted either with monoclonal antibodies, such as rituximab, or downstream of the B-cell receptor with BTK inhibitors including ibrutinib.[9]

Case 1: Man With Acute GVHD

Let’s revisit our case from the beginning of the program to continue our discussion of the management of aGVHD.

Our patient is a 26-year-old man with Ph-positive ALL who undergoes fully matched allogeneic stem cell transplantation from an unrelated donor. He develops an erythematous rash covering more than one half of his body, has watery diarrhea, and has 4 bowel movements daily. He is initially treated with solumedrol, which is the standard of care for aGVHD. After 4 days, his GI tract is worse because he now has 8 watery stools daily.

What is next for this patient? I would say that the best option is to add ruxolitinib and continue the steroids. Let’s review the available evidence supporting this approach.

Existing Therapeutic Options for Treatment of GVHD

What can we do to treat this patient’s aGVHD? The goals are to improve individual organ manifestations, to limit the treatment-related toxicities of our therapies, and to improve the individuals’ functional capacity and quality of life. The standard first-line therapy for aGVHD is corticosteroids. The response to first-line therapy directly correlates with the nonrelapse mortality of patients classified according to treatment outcome, so the individuals who respond early and quickly are those who do the best in the long term.[10]

Survival in Patients With Overall Grade 3/4 Acute GVHD

Outcomes are poor with severe aGVHD, but they have been improving with time, as shown on this slide. On the left are the rates of treatment-related mortality, comparing cohorts from before and after 2007, showing a significant decrease in treatment-related mortality (58% vs 38%; P = .0002) These lower rates correspond with better OS, as shown on the right. This improvement is partially due to improved supportive care measures with better anti-infectives, as well as better HLA matching and improved therapies.[11]

Initial Therapy for Acute GVHD: Steroids With or Without Mycophenolate Mofetil

As noted earlier, corticosteroids are the frontline treatment for aGVHD. Trials adding novel agents to frontline corticosteroids have been performed, but results have been disappointing.

For example, a large phase III trial by the Blood and Marrow Transplant Clinical Trials Network randomized patients with newly diagnosed aGVHD (N = 236) to receive steroids plus mycophenolate mofetil (n = 116) or steroids plus placebo (n = 119) as initial therapy for aGVHD. OS rates at approximately 1 year were lower in patients receiving mycophenolate mofetil vs placebo (OS: 57.8% vs 64.7%, respectively).[12]

REACH1: Study Design

Researchers have had better results in steroid-refractory aGVHD. The REACH1 study was an open-label, single-arm phase II trial of the JAK inhibitor ruxolitinib, which was previously approved for myelofibrosis. Patients 12 years of age or older with grade 2-4 steroid-refractory aGVHD (N = 71) received ruxolitinib plus methylprednisolone; the primary endpoint was an ORR at Day 28 following the initiation of ruxolitinib.[13]

REACH1: ORR at Day 28 (Primary Endpoint)

Study results were positive in this refractory population, with an ORR of approximately 55% (n = 39) at Day 28, with 26.8% (n = 19) having a CR to therapy.[13]

REACH1: OS and Nonrelapse Mortality

Patients had a median OS of 232 days (95% CI: 93 days to not estimable) and a 12-month nonrelapse cumulative mortality rate of 52.9%. Based on results from the REACH1 trial, the FDA approved ruxolitinib for the treatment of steroid-refractory aGVHD.[13]

Most common treatment-related adverse events were primarily hematologic, including anemia (64.8%), thrombocytopenia (62.0%), and neutropenia (47.9%), as well as hypokalemia (49.3%) and peripheral edema (45.1%).

The REACH2 trial, a randomized phase III trial comparing ruxolitinib vs best available therapy in patients with steroid-refractory aGVHD, [14] was recently completed, with positive results reported in a company press release. Full data from this trial, however, are not yet available, but expected in the near future.

GRAVITAS-301: Steroids With or Without Itacitinib as Initial Therapy for Acute GVHD

With proven efficacy of JAK inhibitors in steroid-refractory aGVHD, researchers explored the use of JAK inhibitors in de novo aGVHD with the JAK inhibitor itacitinib, with greater JAK1 specificity than ruxolitinib. The GRAVITAS-301 trial was a randomized, double-blind trial of patients with newly diagnosed aGVHD who were randomized to receive itacitinib plus corticosteroids or placebo plus corticosteroids.[15] The primary endpoint was ORR at Day 28. Unfortunately, although adding itacitinib improved the ORR vs placebo, the ORR primary endpoint and nonrelapse mortality did not reach statistical significance and the study was halted. Adverse effects were consistent with previously reported studies, with thrombocytopenia and anemia being the most common for both the combination and the control.

Abatacept Plus Calcineurin Inhibitor and Methotrexate for GVHD Prophylaxis, Part I

Two related clinical trials have addressed the role of costimulation blockade. The first was an open-label, phase II study done in 43 individuals with 7 of 8 donor HLA-matched transplants. The patients were treated with abatacept plus calcineurin inhibitors (CNIs) and methrotrexate (MTX) with or without antithymocyte globulin (ATG) as primary GVHD prophylaxis. Results from this study were compared with Center for International Blood and Marrow Transplant Research data.[16]

Abatacept Plus Calcineurin Inhibitor and Methotrexate for GVHD Prophylaxis, Part I Results

The results for the abatacept cohort in comparison with the 2 control arms are shown on this slide. The group that received prophylaxis with CNI and MTX is on the left and the group that received prophylaxis with CNI and MTX plus ATG is on the right. The top 2 curves represent the incidence of severe GVHD at 180 days, and what we can see is that the cumulative incidence of severe GVHD is extraordinarily and significantly lower in patients receiving abatacept vs placebo regardless of prophylaxis regimen (CNI plus MTX: 3% vs 32%, respectively; P =.007) and (CNI plus MTX plus ATG: 3% vs 22%, respectively; P = .025). An improvement in disease-free survival (DFS; shown in the bottom 2 curves) was observed in patients receiving abatacept vs placebo in both the CNI plus MTX group (DFS: 79% vs 50%, respectively; P = .0003) and the CNI plus MTX plus ATG group (DFS: 79% vs 63%, respectively; P = .016).[16]

Abatacept Plus Calcineurin Inhibitor and Methotrexate for GVHD Prophylaxis, Part II Results

In the second cohort of this trial, individuals were randomized to receive the addition of abatacept vs placebo. Unlike the first cohort, all of the patients received fully matched (or 8 of 8) unrelated donor transplants. The rates of grade 2-4 and grade 3/4 GVHD were significantly lower and led to an improvement in DFS (shown on the bottom curve).[17]

Case 1: Man With Acute GVHD Revisited

Let’s return to our case. This gentleman has aGVHD that appears to be steroid refractory and appears to have progressed.

What is next for this patient? I would say that the best option is to add ruxolitinib, given the fact that it is the only FDA-approved compound for the management of steroid refractory aGVHD, and continue the steroids. As always, an additional option is to place the patient on a clinical trial if one is available.

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