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CLINICAL FEATURES AND STAGING OF ACUTE GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease (GVHD) occurs after a transplantation: Essentially, the donor’s immune cells attacks the recipient’s cells or organs. There are 2 types of GVHD—acute (aGVHD) and chronic (cGVHD)—and each affects different organs and manifests with different signs and symptoms. The 3 main organs involved in aGVHD are the skin, liver, and gastrointestinal (GI) tract. Historically, aGVHD was defined as developing within 100 days after an allogeneic hematopoietic stem cell transplant (HSCT) and presenting clinically with active symptoms based on the organs involved. However, with the use of more non-myeloablative regimens and donor lymphocyte infusions (DLI), it is clear that aGVHD can have a later onset and can even overlap with cGVHD.

In 2014, the National Institutes of Health (NIH) released new consensus criteria that refined the definitions of both aGVHD and cGVHD and addressed the overlap between them.¹ Now, aGVHD includes (1) classic aGVHD symptoms (erythema, maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea, ileus, or cholestatic liver disease) occurring within 100 days after transplantation or DLI in a patient not meeting criteria for the diagnosis of cGVHD and (2) persistent, recurrent, or late-onset aGVHD (i.e., features of classic aGVHD occurring beyond 100 days post-transplantation or DLI in a patient not meeting criteria for the diagnosis of cGVHD; often seen during the taper or after withdrawal of immune suppression). The term “overlap” refers to the presence of 1 or more aGVHD manifestations in a patient with a diagnosis of cGVHD. Manifestations of aGVHD can be present at initial diagnosis of cGVHD or can develop after the diagnosis of cGVHD and may recur with or without resolution of prior cGVHD manifestations.

The extent of involvement determines the staging of aGVHD. Initially, staging was completed with the NIH scale,² but the most recent grading and staging system is the Mount Sinai Acute GVHD International Consortium (MAGIC) scale (Tables 1 and 2).³

Skin is the most commonly affected organ, often exhibiting an erythematous, maculopapular rash. In severe cases, the skin may blister and ulcerate. GI aGVHD is often difficult to treat and may present as nausea, vomiting, anorexia, diarrhea, and/or abdominal pain. It may involve any or all of the intestine and/or stomach. Lower GI aGVHD generally results in secretory diarrhea, which can be several liters a day, and may cause significant GI bleeding as a result of mucosal ulceration. Upper GI aGVHD is only classified as stage 0 if there is no or intermittent nausea, vomiting, or anorexia, and it is classified as stage 1 if there is persistent nausea, vomiting, or anorexia.³ Liver aGVHD is often difficult to distinguish and is often assumed if other organs exhibit signs of GVHD. Generally, an increase in liver function enzymes and/or bilirubin are the initial signs, followed by jaundice.

Confidence levels of a GVHD diagnosis are assigned as possible, probable, or confirmed. “Possible” indicates that a diagnosis of GVHD is under consideration but not confirmed by biopsy; the clinical suspicion for GVHD is not sufficiently high that the treating physician initiates GVHD therapy. A confidence level of “probable” reflects that treatment for GVHD was started due to sufficient clinical concern, but the diagnosis is not confirmed by biopsy, either because no biopsy was obtained or because GVHD is not clearly identified on a biopsy. GVHD is considered “confirmed” if there is unequivocal evidence of GVHD on a biopsy.

INCIDENCE, MORBIDITY, AND MORTALITY OF AGVHD

The incidence of grade II through IV aGVHD is approximately 40% in matched related donor transplant and up to 60% in matched unrelated donor transplants. The main risk factors for aGVHD include greater degree of human leukocyte antigen (HLA) mismatch, increased age of the patient or donor, myeloablative conditioning regimens, GVHD prophylaxis with a calcineurin inhibitor (CI) and mycophenolate, donor parity, and recipient cytomegalovirus (CMV) seropositivity.⁴

Developing aGVHD is a risk factor for developing cGVHD, which is the primary cause of late morbidity and mortality. A recent retrospective analysis evaluated the inpatient healthcare resource utilization, costs, and mortality in adult patients with aGVHD, including high-risk (HR) and steroid-refractory (SR) aGVHD.⁵ The analysis included 906 adults with aGVHD, 158 with HR/SR aGVHD, and 1529 with no GVHD. Patients who developed GVHD during the initial hospital admission had significantly longer median lengths of stay (31 days for aGVHD and 46 days for HR/SR GVHD vs. 24 days for no GVHD). During the first 100 days after HSCT, patients with aGVHD and HR/SR aGVHD also had significantly higher readmission rates (78.3% and 77.2% vs. 28.3%; P<0.0001) and inpatient mortality rates (20.2% and 35.4% vs. 8.9%; P<0.0001) than patients with no GVHD.

The additional immunosuppression required to treat the GVHD significantly increases the risk of bacterial, viral, and fungal infections, which also cause increased morbidity and mortality. Patients with classic aGVHD, association of visceral organ involvement, greater severity of aGVHD at onset, and advanced disease status have lower survival with severe grade III or IV aGVHD, especially if the disease affects the GI tract, which is associated with up to 75% to 90% mortality.⁶ While severe GVHD significantly increases morbidity and mortality, it is also an important immunologic response that provides for graft-versus-tumor or graft-versus-leukemia effects.

PATHOPHYSIOLOGY OF AGVHD PROVIDES RATIONALE FOR DRUG THERAPIES

GVHD develops as a result of donor T-cells from an allogeneic HSCT attacking recipient tissues due to mismatched major and/or minor histocompatibility antigens between the donor and recipient.⁷ The major histocompatibility complex contains the genes that encode tissue antigens. In humans, the HLA region lies on the short arm of chromosome 6 and consists of Class I HLA (A, B, and C) proteins, which are expressed on almost all nucleated cells, and Class II (DR, DQ, and DP) proteins, which are primarily expressed on hematopoietic cells (activated T-cells, B-cells, dendritic cells, monocytes), but injury or inflammation can induce expression on many types of cells. Now, high-resolution matching is commonly used, which can routinely measure 8 or 10 antigens; greater matches have been shown to decrease GVHD and increase survival after HSCT.^8,9 However, the incidence of aGVHD still ranges from 26% to 32% in recipients of sibling donor grafts and from 42% to 52% in recipients of unrelated donor grafts, even with identical major HLA matching, which demonstrates that other factors are clearly important in the development of GVHD.

aGVHD involves a complex network of inflammation and cellular interactions of both innate and adaptive immunity. Three sequential phases have been described, including activation of antigen presenting cells (APCs); donor T-cell activation, proliferation, differentiation, and migration; and, finally, target tissue destruction.¹⁰ Understanding these phases, and the related molecular processes, is essential for rationalizing potential drug targets and therapies for aGVHD.

Phase 1: activation of APCs

In the first phase of aGVHD, APCs, including dendritic cells, monocytes, macrophages, neutrophils, and Langerhans cells, are activated.¹¹ Triggers of this response are from danger-associated molecular pattern molecules, such as tissue injury from the conditioning regimen, or from pathogen-associated molecular pattern molecules, such as the release of bacteria from the GI tract, as well as inflammatory molecules, such as lipopolysaccharides, and changes in the GI microbiome. The end result is increased cytokine activation including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1, and chemokines such as CCL2-5 and CXCL9-11. Early in transplant, around the time of engraftment, a cytokine storm or engraftment syndrome may occur, which is an early-phase GVHD that increases the risk of severe GVHD and mortality.¹²

Phase 2: donor T-cell activation, expansion, and trafficking

The donor T-cells interact with the APCs from phase 1 to cause T-cell activation, proliferation, and differentiation.¹³ While much emphasis has been placed on the CD8+ T-cells, there may be several types of T-cells involved, including CD4+ T-cells, T helper (Th) cells, such as Th1, Th2, Th17, and T follicular helper cells, and the GVHD-suppressing regulatory T-cells (Tregs). This is all controlled by cytokines secreted by the activated T-cells. These cytokines are classified as Th1 (interferon [IFN]-γ, IL-2, and TNF-α) or Th2 (IL-4, IL-5, IL-10, and IL-13) and Th17 (IL-17). It is clear that the cascade of Th1 cytokines can induce GVHD, but the balance of Th1 and Th2 cytokines is important, as well.⁷ While much work is still needed to fully understand these critical pathways, multiple cytokines cause and regulate the severity of GVHD, depending on the timing, levels, and duration of exposures.

During phase 2, T-cells also start to move from the lymphoid system to target tissues through chemokine signaling, such as CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11, and then bind by adhesion molecules like integrins. This process can explain why certain organs are specifically targeted for GVHD. For example, T-cells are driven to the GI tract by α4β7 integrin.

Phase 3: cellular and inflammatory effector phase

In phase 3, cytokines developed earlier amplify the cellular and inflammatory mediators, causing T-cells, neutrophils, macrophages, natural killer (NK) cells, and NK-T-cells to damage tissues and organs.¹³ Cytotoxic T-cells use the Fas/Fas ligand (FasL) and perforin/granzyme pathways to lyse target cells.¹⁴ Interestingly, it appears that the perforin/granzyme system is more dominant in the skin and GI tract, while the FasL system may be predominant in the liver, which may lead to different strategies for treatment.¹⁵

In this phase, there still continues to be secretion of many inflammatory cytokines, especially TNF-α, which can also drive effector cells to target organs and directly cause tissue damage via apoptosis and necrosis.

THERAPEUTIC APPROACHES IN THE TREATMENT OF AGVHD

Several therapies are available for the treatment of aGVHD. The approaches to treatment can be divided into first- and second-line therapies.

First-line therapy for aGVHD

For most grade II to IV aGVHD, or any disease with visceral involvement, initial treatment continues to be methylprednisolone 2 mg/kg or equivalent steroid and a CI, either cyclosporine or tacrolimus.¹³ In certain cases of limited, low-grade aGVHD, like grade I skin GVHD, systemic steroids can be initially spared with the use of topical steroids alone. For only upper GI GVHD, which is usually more responsive to steroids, often methylprednisolone 1 mg/kg can be effective. Despite high-dose steroids being the standard of care for more than 25 years, responses are poor, with only 44% of patients with grade II to IV disease achieving a complete response (CR) or partial response (PR).¹⁶

A phase II randomized trial comparing steroids and a CI with either etanercept, mycophenolate, denileukin, or pentostatin showed that mycophenolate had a clinical benefit over the others; however, this trial did not have statistical power to absolutely predict a superior therapy.¹⁷ With these results, a randomized phase III trial added mycophenolate to steroids and a CI as initial therapy without benefit compared to steroids and CI alone.¹⁸

Also controversial is the schedule for steroid taper. One prospective randomized trial compared steroid taper over 86 versus 147 days after initial response to treatment. The long taper achieved resolution in 30 days, compared to 42 days with the short taper. Steroids cause significant toxicities, including hypertension, hyperglycemia, edema, bone breakdown, and cataracts, and they cause a significantly higher risk for infections, especially fungal and viral infections. Since the response to initial therapy correlates directly with post-transplant survival, it is imperative to find more effective first-line therapies, as well as effective second-line therapy.¹⁹

Second-line therapy for aGVHD

With the high rates of SR GVHD, which is defined as progressive disease after 3 days of treatment, stable disease after 7 days of treatment, or partial response after 14 days of treatment with steroids, the majority of patients require second-line treatment. Until recently, there have been no drugs approved in this setting and there has been no consensus as to which therapy should be used. However, in 2019, the United States Food and Drug Administration (FDA) approved the Janus kinase 1 and 2 (JAK1/JAK2) tyrosine kinase inhibitor ruxolitinib for treatment of SR aGVHD.²⁰ The mechanisms of action of ruxolitinib cover several aspects of the 3 phases associated with aGVHD. A potential advantage of ruxolitinib over specific targeted therapies is the inhibition of several cytokines, including TNF, IL-2, IL-6, and IFN- γ, which utilize the JAK-STAT pathway for activation of cellular activity; therefore, blocking this path should significantly decrease their critical roles in GVHD.²¹ (Ruxolitinib also impairs differentiation of CD4⁺ T-cells into IFN-γ- and IL-17A-producing cells, thus decreasing activity of GVHD while increasing FoxP3⁺ regulatory T-cells, which are important in immunologic tolerance.)

The approval of ruxolitinib was based on the REACH1 study—a prospective, open-label, single-cohort, multicenter study of ruxolitinib in 71 patients 12 years and older with grades II to IV SR aGVHD.^22,23 Grading was based on the MAGIC criteria. SR was defined as patients who had GVHD that progressed after 3 days of at least 2 mg/kg/day of methylprednisolone or equivalent, had disease that failed to improve after 7 days of at least 2 mg/kg/day of methylprednisolone or equivalent, were treated with at least 1 mg/kg/day of methylprednisolone for skin GVHD or skin plus upper GI GVHD and developed disease in an additional organ, or were unable to achieve a 50% taper of their steroid dose without a return of their GVHD. Ruxolitinib was initiated at 5 mg orally twice daily and increased to 10 mg twice daily on the fourth day if the absolute neutrophil count and platelet counts were not decreased by 50% or more relative to the first day of dosing and treatment-related toxicity was not observed. Ruxolitinib was administered for a median of 46 days (range, 4-382 days). Steroid taper was according to individual institution guidelines. The primary endpoint was overall response rate (ORR; CR, PR, or very good partial response) at day 28 based on the Center for International Blood and Marrow Transplant Research (CIBMTR) definitions (Table 3); ORR was evaluable in 49 of the patients in the trial who were refractory to steroids alone.^20,24

At baseline, aGVHD was grade II in 27% of patients, grade III in 55%, and grade IV in 18%, and 84% of patients had visceral GVHD. The median duration of prior corticosteroid exposure at baseline was 15 days (range, 3-106 days). Day 28 ORR was 57.1% in all 49 patients and was 100% for grade II GVHD, 40.7% for grade III GVHD, and 44.4% for grade IV GVHD. The median duration of response, calculated from day 28 response to progression (defined as worsening by 1 stage in any organ without improvement in other organs in comparison to prior response assessment), new salvage therapy for aGVHD, or death from any cause, was 16 days. Those who responded had a median of 173 days from day 28 response to either death, need for new therapy, or increase in steroids for aGVHD. Adverse reactions are shown in Tables 4 and 5. The most common grade 3/4 reactions were myelosuppression (anemia [45%], thrombocytopenia [60%], neutropenia [40%]), infections (41%), hemorrhage (20%), hypertension (13%), and thrombosis (11%). Discontinuation due to adverse reactions was observed in 31% of patients on ruxolitinib, with infections leading to the highest rate of treatment discontinuation (10%).²⁰

While ruxolitinib is currently approved for patients over 12 years of age, it has been evaluated retrospectively for SR aGVHD in 13 pediatric patients aged 1.6 to 14 years.²⁵ One patient achieved a CR, 4 had a PR, and 2 had no response at 4 weeks after the first ruxolitinib dose for an ORR of 45% at 1 month, with 9% achieving CR. Seven of 13 patients were alive at a median follow-up of 401 days after HSCT, with 4 patients having no GVHD symptoms and 2 being able to stop all immunosuppression. The median time to starting therapy was 106 days after median aGVHD onset, and patients were refractory to steroids and at least 2 other agents. Ruxolitinib was initially administered orally at 5 mg twice daily for children weighing at least 25 kg or 2.5 mg twice daily if they weighed less than 25 kg; doses were escalated to 10 mg twice daily in 9 patients and only 1 patient weighed less than 25 kg. 

Other agents for second- or third-line treatment of SR GVHD

Several agents are available for SR GVHD. The choice among agents is based on disease- and patient-specific characteristics.

Tocilizumab

A cytokine that appears to be especially important in causing cytokine release syndrome associated with chimeric antigen receptor T-cell therapy is IL-6. IL-6 baseline and post-transplant levels have also recently been shown to be predictive of increased grade II to IV GVHD and overall survival.²⁶

Tocilizumab, the humanized anti-IL-6 receptor monoclonal antibody has been reported to be effective in SR aGVHD of the lower GI tract.²⁷ In a retrospective study of 16 consecutive adult transplant recipients, tocilizumab 8 mg/kg was administered every 2 weeks until either a CR, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. In all, 62.5% achieved a CR after a median time of 11 days from tocilizumab initiation. Time to improvement by a decrease in at least 1 stage was reported as a median of 1 day. At a median follow-up of 7.6 months from initiation of tocilizumab, 37.5% patients were alive and free of their underlying hematologic malignancy. 

Another small study demonstrated a 44% ORR, but the response was not durable, with a median survival from the start of tocilizumab of 26 days.²⁸ These patients all had grade III to IV GVHD and therapy was not started until a median of 44 days from GVHD onset; tocilizumab was dosed at 8 mg/kg every 3 to 4 weeks. 

The differences in the outcomes of these reports highlight general principles that appear to be important in treating SR aGVHD: Earlier therapy appears to have more efficacy and it is important to try to rapidly maximize receptor binding. Most of the dosing of biologic therapy for GVHD has been adapted from autoimmune disorders, where these agents are approved. In autoimmune disorders, it may be feasible to wait until several doses of these agents are given before any improvement is expected, as these are generally chronic disorders, but, in rapidly progressing disorders like GVHD, it is critical to maximize receptor occupancy rapidly.

Anti-TNF-α agents

One of the earliest targeted biologic therapies for GVHD was TNF-α inhibitors, and most reports are with infliximab, the chimeric monoclonal antibody that binds to either membrane-bound or unbound TNF-α, or etanercept, the soluble dimeric TNF-α receptor 2 inhibitor that only impacts unbound TNF-α.²⁹ This difference causes more inhibition of macrophages, with infliximab resulting in a significant risk of fungal infections, especially aspergillus.³⁰ With many of these biologic therapies, it is critical that appropriate antifungal prophylaxis be a standard part of the regimen.³¹

In a phase III randomized trial of high-dose corticosteroids with or without infliximab that included 63 newly diagnosed GVHD patients, no statistically significant difference was found in GVHD-related mortality, non-relapse mortality, or overall survival.³² In the phase II randomized trial mentioned earlier comparing steroids with etanercept to other agents including mycophenolate in first-line therapy of GVHD, it was shown that mycophenolate was superior.¹⁷ However, in a small study of 13 patients, etanercept had a 46% response rate, with the best responses in GI GVHD.³³

While inhibition of TNF-α is a common therapeutic strategy, the data are not convincing that this is a highly effective therapy in grade II to IV GVHD; it may have higher responses when used for GI GVHD.

Anti-IL-2 receptor antibodies

The majority of patients are either already on a CI or are started back on a CI with the activation of GVHD. Since the CIs cause inhibition of IL-2, it was originally unclear if addition of the monoclonal antibodies that work against IL-2 receptors—daclizumab or basiliximab—would have additional effects. However, daclizumab resulted in a 69% CR rate when given as a single second-line agent to 62 patients with SR aGVHD.³⁴ Interestingly, when daclizumab was evaluated in a randomized trial as initial treatment for aGVHD along with steroids and a CI, the daclizumab arm had lower survival rates at 100 days and at 1 year.³⁵ Daclizumab was voluntarily removed from the market.

Basiliximab is approved as an immunosuppressive agent in solid organ transplant. A few small studies have been completed with basiliximab in aGVHD. In one study of 34 patients with severe SR GVHD, CR occurred in 84% with skin, 48% with GI, and 26% with liver GVHD; however, median duration of response was only 38 days and flares occurred in 41% of patients.³⁶ In another report of 23 patients with SR aGVHD, basiliximab showed an ORR of 82.5%, with 17.5% CR and 65% PR, and flares occurring in 53% of patients.³⁷

Sirolimus

Sirolimus, a mammalian target-of-rapamycin (mTOR) inhibitor, has an advantage of having no inhibitory effect on Treg cells, thus, potentially helping to increase tolerance.^38,39 The majority of studies for GVHD have combined sirolimus with steroids and a CI, which decreases Tregs, taking away one of the advantages of sirolimus. In a retrospective study of 21 patients, sirolimus did produce a 57% ORR, with 24% CR, in grade III to IV SR aGVHD.⁴⁰

Toxicities make sirolimus difficult to use in patients with GVHD, especially with steroids. While hyperlipidemia and hypertriglyceridemia are very common effects, it is thrombotic microangiopathy that is generally most concerning and may be easily overlooked for a period of time. It should be noted that there has been a case of severe, life-threatening hypertriglyceridemia with the combination of sirolimus and ruxolitinib.⁴¹ Also, there is concern of longer-term cardiac issues in these patients, and, potentially, the increased cholesterol could even lead to worsening of GVHD.⁴² Further, the risk of having inflammatory pulmonary toxicity is worrisome, especially if a patient has any active lung GVHD.

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody to CD52, which is expressed on B-cells, T-cells, NK cells, and dendritic cells, and causes extreme lymphopenia. While it would be expected that this should resolve active GVHD, the results tend to show ORRs of approximately 50% to 60%; however, they are associated with an extremely high infection risk and mortality rate. The largest report to date is from a study of 55 patients with SR aGVHD treated over a 14-year span.⁴³ Initially, doses of up to 191 mg were given, but, more recently, patients were treated on the basis of response, starting with doses of 3 to10 mg that were repeated every 7 to 14 days for 3 to 4 doses. Overall, 62% of patients died of either infection and/or GVHD; 30% did achieve response, but 40% of those relapsed. This demonstrates the delicate balance of immunosuppression that makes treating GVHD so difficult.

One prospective study of 18 patients with SR aGVHD received alemtuzumab 10 mg daily for 5 days. Overall, 83% of patients had a response by 1 month and 55% were alive at 11 months. Infections occurred in 78% of patients, including CMV reactivation in 61%.⁴⁴ While alemtuzumab does have efficacy, it is important to note that mortality appears to increase significantly due to infection and patients receiving alemtuzumab should have broad-spectrum antimicrobial prophylaxis, with a strong consideration for letermovir, as well. A risk-adapted approach using lower doses of alemtuzumab needs to be studied to determine if this would be a more feasible strategy to limit toxicities.

Antithymocyte globulin

Multiple retrospective studies have shown some benefit of antithymocyte globulin (ATG) in SR disease.^45,46 In a prospective randomized trial, 61 patients with aGVHD refractory to 2 mg/kg/day of methylprednisolone were treated with 5 mg/kg/day methylprednisolone alone or in combination with rabbit ATG. There was no difference between the 2 arms in terms of response rates or survival.⁴⁷ Another center used response-guided therapy with rabbit ATG in 11 patients; ATG was initially given at 1 mg/kg with gradual dose escalation depending on response.⁴⁸ The ORR was 55% at 1 month, with a median of 2 doses of ATG and a median dose of 3 mg/kg (range 1-11.75 mg/kg). As with other trials, skin disease had high rates of response (100%; 3/3 patients), and an 83% response rate was seen with GI GVHD; however, liver disease only showed a 25% response. The overall survival at 1 year was 55%.

Historically, ATG has been shown to increase the risk of developing post-transplant lymphoproliferative disorder, so Epstein-Barr virus copy numbers should be monitored routinely in patients receiving this therapy.

Combination therapy

Data are very limited on combination therapy approaches for treatment of refractory GVHD beyond combinations with steroids. Many patients end up receiving combination therapy at some point, often unintentionally. Most antibodies used for GVHD have long half-lives after reaching steady state, and, in general, most of these drugs will have levels available for at least 3 to 4 weeks.⁴⁹ When therapies are “changed,” it is important to realize that there could be a long overlap of effect, so, at that point, it becomes combination therapy.

Because of the importance of IL-2 and TNF in GVHD, there have been small studies specifically combining these therapies. They are often reported to have higher response rates but they may also have higher adverse event rates, especially increased infections, and broad-spectrum prophylaxis is critical.³¹ In one study, 12 patients were treated with daclizumab alone or in combination with infliximab. Prophylactic cyclosporine and mycophenolate were also continued and prophylactic bacterial and fungal anti-infectives were given. The 200-day mortality was 17%, compared to 89% in a historical matched cohort of 12 patients treated with ATG and mycophenolate mofetil.³¹ In another trial, combination daclizumab and infliximab resulted in an 86% response rate in severe GI GVHD.⁵⁰

GI-specific therapies for GVHD

GI GVHD occurs in up to 60% of transplants and may cause anorexia, malnutrition, severe diarrhea, and GI bleeding. It is often refractory to steroids, and grade III to IV disease may cause mortality in over 70% of patients.⁵¹ Oral budesonide (Entocort), approved for use in Crohn’s disease, is an enteric-coated capsule, formulated to dissolve at high pH, which allows delivery to the intestines; it is available as 3-mg capsules and is generally dosed as 3 mg 1 to 3 times daily for GVHD.⁵²

A newer budesonide product (Uceris) is an extended-release, enteric-coated tablet; it has delayed-release beads, which potentially allows for more drug to reach lower into the intestines and colon, where GVHD may be more prevalent.⁵³ It is only available in 9-mg capsules, so it is generally dosed as 9 mg daily.⁵⁴

While budesonide has not been evaluated in randomized trials, a similar agent, beclomethasone has. A phase III trial compared immediate-release and sustained-release beclomethasone at a dose of 2 mg every 6 hours with prednisone to prednisone 1 mg/kg/day and placebo for 10 days then tapered over 7 days.⁵⁵ Responses occurred in 69% of the beclomethasone arm and 52% of the placebo arm. Mortality was significantly better with beclomethasone, with hazard ratios (HR) of 0.33 (p=0.001) at day 200 and 0.54 (p=0.04) at 1 year. Beclomethasone also resulted in a faster prednisone taper.

Budesonide (Entocort) in conjunction with systemic steroids was evaluated retrospectively in 22 patients and compared to 19 historical controls.⁵⁶ Budesonide resulted in an ORR of 77% and the historical control achieved a response rate of 32%. Budesonide also allowed a faster taper of systemic steroids.

Recently, vedolizumab, a monoclonal antibody directed against α4β7 integrin, was approved by the FDA for inflammatory bowel disease.⁵⁷ Donor T lymphocytes, which express α4β7 integrin, will migrate to lymphoid tissues of the GI mucosa and this trafficking may be inhibited by blocking the α4β7 integrin. In a patient with only active GI GVHD, it would be ideal to specifically cause local immunosuppression, thus limiting potential complications of systemic suppression. Retrospective data from multiple centers evaluated the use of vedolizumab in 29 SR GI aGVHD patients, most of whom had stage II to IV disease.⁵⁸ A median of 3 doses of 300 mg was given: an ORR of 64% at 6 to 10 weeks and overall survival of 54% over 6 months were achieved. Several infections (8 nonserious and 1 serious) were reported: GI origin was confirmed in 8 patients. While larger trials would be beneficial, this is an intriguing therapy to help treat localized GI GVHD.

PHARMACISTS’ ROLES IN THERAPY MANAGEMENT

Pharmacists have been incorporated into and are critical members of the HSCT multidisciplinary team, and, in fact, they are required by the Foundation for the Accreditation of Cellular Therapy and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT)-European Society for Blood and Marrow Transplantation (EBMT) (FACT-JACIE) international standards for hematopoietic cellular therapy product collection, processing, and administration. A summary of roles and responsibilities of pharmacists from the American Society for Blood and Marrow Transplant describe core competencies and aims for interventions (Tables 6 and 7).⁵⁹

Assessment of drug interactions

Pharmacists are keenly aware of drug interactions and, as such, must closely monitor for appropriate dosing of all drugs. In a patient with GVHD, many drug interactions are possible: Pharmacists must realize this risk, make necessary adjustments, and monitor drug levels appropriately. The Infectious Disease Society of America guidelines recommend prophylactic posaconazole in GVHD patients who are receiving steroids. Commonly, voriconazole or isavuconazole may be used. While all of these azoles are inhibitors of cytochrome P450 (CYP), voriconazole and posaconazole have stronger inhibitory effects. Additionally, monitoring is important with tacrolimus and cyclosporine, which commonly increase the area under the curve (AUC) by 200% to 300%, and with sirolimus, which can increase the AUC 10-fold: It is critical that pharmacists appropriately monitor levels of these agents, as well as the azoles.

Monitoring for drug interactions is also important with ruxolitinib, which is cleared by CYP3A4 and CYP2C9.²⁰ Simulations described in the ruxolitinib package insert suggest that 100 mg to 400 mg of fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increase steady-state ruxolitinib AUC by approximately 100% to 300% and ketoconazole (a strong CYP3A4 inhibitor) increases the ruxolitinib maximum concentration by 33% and the AUC by 91% and prolongs its half-life from 3.7 hours to 6 hours.²⁰

Very unique interactions may also occur. For example, oral budesonide, which is often incorrectly described as a “non-absorbable steroid,” is a low-bioavailable steroid due to high first-pass metabolism, primarily by CYP3A4.⁵⁰ This first-pass effect will be significantly decreased by voriconazole or posaconazole, resulting in high bioavailability of the potent budesonide steroid. Serum levels should be monitored with this combination, since 9 mg of budesonide could be equivalent to over 100 mg of prednisone.

A primary understanding of kinetic principles is also key. Mycophenolate, commonly used in transplant patients, relies on enterohepatic resorption to maintain adequate levels.⁶¹ Patients with GI GVHD may have liters of diarrhea, making this process nearly impossible and resulting in low to non-existent levels of mycophenolate. While changing to IV mycophenolate may be a consideration, its metabolism must be understood: Metabolism is complete within an hour and, again, without enterohepatic resorption, there still would not be adequate levels of active drug.

Education of patients and healthcare providers

Pharmacists need to take a lead role in both patient and provider education. As medication experts, it is important that pharmacists are comfortable communicating with multiple audiences so that the patient, the nurse, the nurse practitioner or physician assistant, and the physician all have conversations at appropriate levels of knowledge and understanding.

It is also critical that pharmacists be active not only in direct patient care but also in research, such as in designing and helping to ensure adequate dosing of agents in new trials. For example, understanding that cytokine levels in active GVHD are most likely much higher than in chronic autoimmune conditions and that agents used in those settings that interact with cytokines may need either higher doses or more frequent administration in GVHD, where high cytokine levels need to be decreased quickly to have the best effect.

Pharmacists may also be key liaisons between teams, especially when considering risks of infections. Expertise in drugs and infectious diseases are inseparable in HSCT, and pharmacists can work with multiple teams to develop clinical practice guidelines.

Supportive care is also extremely important during transplants. For example, many patients experience nausea and vomiting at a variety of time points during the transplant process.⁶² Pharmacists should understand that serotonin antagonists slow down GI motility and can be effective management for nausea and vomiting; however, serotonin is generally only a driver of side effects early in transplant care, so other agents may be required later. Additionally, many specialized therapies have unique effects, such as hypertriglyceridemia with both ruxolitinib and sirolimus, so strategies to monitor and treat these effects are critical.

It is also essential that, as members of a multidisciplinary HSCT team, pharmacists help to follow outcomes over time, such as evaluating infections at individual institutions and determining if prophylactic regimens may need to be changed. One area that is often overlooked in transplant care is bone health, so developing protocols to manage this is an example that could greatly decrease long-term complications from the steroids used for GVHD. Also, monitoring plans for blood glucose levels with steroid use are important, since many patients develop steroid-induced diabetes. Further, pharmacists can evaluate outcomes in areas that may not have much literature, such as outcomes of HSCT in patients who have had bariatric surgeries. Such roles allow excellent opportunities for cooperation with other colleagues in healthcare, such as dieticians, and special projects in these areas often provide chances for residents or pharmacy students to contribute to investigations.

Perhaps one of the most difficult, but essential, roles of clinical pharmacists is to help patients establish treatment expectations. Pharmacists need to be able to explain both the expected outcomes of therapy, as well as the time frame in which the outcomes may be achieved; at the same time, pharmacists must try not to overwhelm, discourage, or provide a false sense of security. For example, it easy to tell a patient with isolated grade I skin GVHD that the skin is expected to get better in just a few days with a topical steroid, but a pharmacist also needs to explain that there is a possibility that the disease could progress; the patient should be instructed to inform the clinic of any worsening of the current area being treated, and the pharmacist should ensure the patient understands that the area being treated can get better but other areas of the skin may begin to be involved over the next several days or even weeks.

Discussing GI GVHD with patients is often more difficult than discussing skin disease. For example, a pharmacist must explain to a patient with grade III or IV GI GVHD that the steroids only have an approximately 50% chance of working and that the next 3 to 5 days are critical in determining if more therapy is required. In this scenario, a patient must have a realistic expectation that treatments could last for several weeks and, possibly, even months, and that, unfortunately, some patients will succumb to the GVHD.

Patients often greatly appreciate having even a basic understanding of the mechanisms of GVHD and its treatments so that they understand why therapies are changed or added and so that they understand and anticipate what may be ahead in their care. Pharmacists must also provide patients with expectations of the side effects that may develop. Many patients feel that they are being barraged with setbacks and, if none of these are anticipated, they may be difficult for patients to handle emotionally. Understandably, depression may develop in these patients, so it is also important for pharmacists to help evaluate mental health and provide appropriate recommendations for care, if treatment is necessary.

Pharmacists play a role in helping to maintain drug costs, as well as overall healthcare costs. It is not unusual that clinical pharmacists are charged with developing 1 to 2 cost-savings programs every year, and this may be especially important for pharmacists in an HSCT setting, in which the majority of transplants are contracted for a specified amount. A recent analysis evaluated the inpatient healthcare resource utilization, costs, and mortality in adult patients with aGVHD including HR/SR GVHD.⁵ The analysis included 906 adults with aGVHD and 158 with HR/SR aGVHD. Patients who developed GVHD during the initial hospital admission had significantly longer median lengths of stay (31 days [aGVHD] and 46 days [HR/SR aGVHD] vs. 24 days [no GVHD]) and higher median total costs ($153,849 and $205,880 vs. $97,417) than patients with no GVHD (all P<0.0001). During the first 100 days, patients with aGVHD and HR/SR aGVHD also had significantly higher readmission rates (78.3% and 77.2% vs. 28.3%; P<0.0001) and inpatient mortality rates (20.2% and 35.4% vs. 8.9%; P<0.0001) than patients with no GVHD.

Many patients with SR aGVHD need to be admitted for therapy because the majority of agents are administered intravenously; they may also be difficult to administer as an outpatient, they may not be covered by insurance, or there may not be enough time to obtain insurance approval. Strategies to use additional oral medications quickly with SR aGVHD may help to decrease admissions and save costs. This strategy now may be available with the approval of ruxolitinib for aGVHD. Prior authorizations and high copays may still be problems, so a work-flow should be created to start this process at the time of GVHD diagnosis or, perhaps, even pre-emptively in high-risk patients. This is also true for supportive medications that may be required with the onset of GVHD or with the use of more immunosuppression, such as extended-spectrum azoles or CMV prophylaxis with letermovir.

Unfortunately, it is often difficult to get funding for pharmacist positions. A study evaluating the impact of pharmacists in HSCT found that pharmacist intervention, through formulary management and discharge prescription service, leading to prescriptions filled at the institution resulted in average revenue of $990 per patient through the outpatient pharmacy.⁶³ In the outpatient clinic, pharmacist visits generated an additional $23,000 in charges (approximately $80 per patient) and an annual prescription revenue of approximately $840,000 through the outpatient pharmacy. Pharmacists’ activities also led to 122 hours of time savings for providers.

SUMMARY

aGVHD occurs in approximately 40% to 60% of allogeneic HSCT recipients and remains a common life-threatening complication.⁶⁴ The process occurs as a result of donor T-cells recognizing recipient tissue and cells as foreign. The biology and pathogenesis that cause aGVHD are complicated and involve a critical role of cytokines. There are numerous targeted therapies available for these cytokines, each with unique features, toxicities, and kinetics. Pharmacists are critical and valuable members of the HSCT team and are expected to optimize patient outcomes through education, medication management, and research.

Update: July 1, 2020 Results from the REACH2 study were published – a multicenter, randomized, open-label, phase III study of ruxolitinib in 309 patients 12 years of age and older with SR aGVHD.  The primary endpoint of overall response at day 28 was higher in the ruxolitinib group (62%) than the control group (39%)(95% CI, 1.65-4.22; P<0.001). Complete responses were observed in 53 patients (34%) in the ruxolitinib group versus 30 patients (19%) in the control group.  Durable overall response at day 56 was observed in 61 patients (40%) in the ruxolitinib group versus 34 patients (22%) in the control group (odds ratio, 2.38; 95% CI, 1.43-3.94; P<0.001). Reference: Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382:1800-1810. 9;30(suppl 5):11920.

Update: March 4, 2020 T-Guard has been granted Orphan Drug and Fast Track designation by the FDA for steroid-refractory acute graft-versus-host disease in patients following allogeneic stem cell transplantation. This approval was based on the phase I/II study by Groth et al. in Biology of Blood and Marrow Transplantation that showed T-Guard can specifically identify and eliminate mature T cells and NK cells with minimal treatment-related side effects. [Groth C., et al. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):712-719. doi: 10.1016/j.bbmt.2018.10.020. Epub 2018 Nov 3.]

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