Updates in Chronic Graft-Versus-Host Disease: Novel Treatments and Best Practices in the Current Era

Abstract

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplant. The development of cGVHD involves a complex, multistep process that is characterized by early inflammation and tissue injury, followed by chronic inflammation, aberrant tissue repair, and fibrosis. Systemic corticosteroids remain the first line of treatment for cGVHD. New treatments for patients with cGVHD for whom treatment has failed or who develop steroid-dependent cGVHD are now available; these include ibrutinib, ruxolitinib, and belumosudil. Treatment selection may be based on the patient’s individual needs, graft-versus-host disease organ involvement, and comorbidities. However, as therapeutic options for patients without a treatment response or with only a partial response remain an unmet need, new agents are under investigation. Furthermore, patients with cGVHD can develop multiorgan involvement and frequently require specialized care. A multidisciplinary team approach that focuses on the individual’s needs and quality of life is strongly encouraged.

Introduction

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplant (alloHCT) that occurs because of profound immunologic dysregulation.¹ cGVHD occurs in 30%−70% of patients, depending on the type of conditioning, donor source, human leukocyte antigen matching, and graft-versus-host disease (GVHD) prophylaxis regimen.^2,3,4 According to a recent analysis of claims data, approximately 15,000 patients are currently experiencing active cGVHD in the United States.⁵ This review outlines an understanding of the immunobiology of cGVHD and details the current treatment options. The goal of this review is to provide guidance for a systematic and collaborative approach for the management of patients with cGVHD.

Pathophysiology of cGVHD

The development of cGVHD involves a complex, multistep process characterized by 3 phases: (1) early inflammation and tissue injury, (2) chronic and aberrant tissue repair, and (3) fibrosis.¹ The first phase occurs primarily because of early tissue damage.⁶ This damage triggers an inflammatory response that drives both innate and adaptive immune processes (Figure 1). The release of inflammatory cytokines, such as interleukin (IL)–1, IL-2, IL-17, and TNF-α, from injured tissue and the release of both pathogen- and damage-associated molecular pattern molecules are key drivers of this early innate immune response.^6,7 Secretion of IL-17 further promotes secretion of IL-6 and IL-8, which results in expression of adhesion molecules, major histocompatibility complex (MHC) class antigens, and costimulatory molecules. Antigens that enter systemic circulation interact with Toll-like receptors, which then upregulate MHC class II and costimulatory molecules on host antigen-presenting cells.⁶ Antigen-presenting cells present these host antigens to alloreactive donor T lymphocytes. These primed donor T-cells then undergo further activation, differentiation, and expansion. The combination of IL-6, IL-1, and transforming growth factor-beta (TGF-β) upregulates the transcription factor RORγt, which results in T helper cell 17 (Th17) differentiation. Th17 cells then secretes proinflammatory cytokines, such as IL-17A, IL-17F, and IL-22. Secretion of these proinflammatory cytokines, along with cytotoxic T lymphocytes, results in damage to target tissues.

Fig. 1: Pathophysiology of chronic graft-versus-host disease.

Chronic GVHD involves 3 phases: early inflammation and tissue injury, chronic inflammation and dysregulated immunity, and fibrosis and improper repair. α-SMA alpha smooth muscle actin, Ag antigen, Allo allogeneic, APC antigen-presenting cell, BAFF B-cell activating factor, BCR B-cell receptor, CTGF connective tissue growth factor, DAMP damage-associated molecular pattern, HCT hematopoietic cell transplant, PAMP pathogen-associated molecular pattern, PDGF platelet-derived growth factor, PDGFR-α platelet-derived growth factor receptor alpha, Tfh T follicular helper, TGF-β tumor growth factor beta, Th T helper.

The second phase of cGVHD is marked by pronounced dysregulation of the immune response and reconstitution resulting from impaired tolerance between donor immune cells and the host (Figure 1). This loss of tolerance starts when conditioning chemotherapy causes thymic damage and reduces negative selection of autoreactive T-cell clones.⁸ The decrease in regulatory T-cells, secondary to prolonged use of calcineurin inhibitor and dysregulated self-antigen presentation, allows autoreactive T-cells to further propagate cGVHD.^9,10,11 The tolerance mechanisms for B-cells are similarly dysfunctional in cGVHD. In the early post-hematopoietic cell transplant period, high circulating levels of B-cell activating factor are present, which promotes survival of autoreactive transitional B-cells.¹² In addition, B-cell activation via B-cell receptor signaling is increased and causes autoreactive B-cells to produce autoantibodies against different targets (e.g., platelet-derived growth factor receptor).^13–16 Some of these antibodies have been found in patients with sclerotic GVHD and bronchiolitis obliterans.^13,17,18 Proliferation and differentiation of these B-cells to memory B-cells and plasma cells are driven by activated T follicular helper cells.¹⁹ The loss of tolerance in B- and T-cells is interrelated in propagation of the cGVHD cascade.

The final phase of cGVHD results from the activation of macrophages that produce TGF-β and platelet-derived growth factor alpha, leading to myofibroblast reactivation (Figure 1).^1,20 Macrophages are an essential component of normal tissue repair and have been shown, in both preclinical and clinical disease models, to accumulate in fibrotic lesions.^21,22,23 Activated fibroblasts produce collagen in the extracellular matrix, which ultimately leads to fibrosis.¹ This state of chronic inflammation is mediated by Th17 cells.^24,25,26 Th17 cells are dependent on the RORγt and STAT2 signaling pathways, which further promotes cGVHD.^24,27

Diagnosis of cGVHD

The diagnosis of cGVHD is based on clinical features, but diagnosis may be challenging because signs and symptoms of cGVHD are variable and can simulate other disorders, such as autoimmune diseases. The National Institutes of Health consensus established standardized diagnostic criteria for cGVHD; these include the presence of signs and symptoms that are unequivocal or diagnostic, such as mouth lichen planus in oral cGVHD and poikiloderma in skin cGVHD.^{28, 29} However, the presence of distinctive features of cGVHD is insufficient to establish a diagnosis alone; diagnosis requires laboratory or biopsy confirmation or the concurrent involvement of another organ or site with diagnostic features of cGVHD. Organs that may be affected by cGVHD include the skin, mouth, eyes, gastrointestinal (GI) tract, liver, lungs, joints and fascia, and genital tract. In addition, other clinical features or complications have been attributed to cGVHD but are often a diagnosis of exclusion; these include ascites, pericardial and pleural effusion, nephrotic syndrome, myasthenia gravis, peripheral neuropathy, and polymyositis.³⁰ The severity of cGVHD is assessed by individual organ scores, from 0 (no symptoms or features) to 3 (worst symptoms or features). In contrast, the global severity of cGVHD includes all 8 organs or sites for the score calculation of either mild, moderate, or severe cGVHD.^{29, 31}

Treatment for cGVHD

First-Line Therapy: Corticosteroids

The primary goals of treatment for cGVHD are to decrease activation of B- and T-cells, decrease inflammation, slow the development of fibrosis, and improve quality of life.³² In the long term, cGVHD-directed therapy should achieve a state of immune tolerance that allows for successful withdrawal from immunosuppressive therapy without relapse. Corticosteroids have been used as front-line treatment for decades and possess potent anti-inflammatory and immunosuppressive properties.²⁸ The recommended starting dose for corticosteroids is 0.5 to 1 mg/kg/day of methylprednisolone (or prednisone dose equivalent).^{33, 34} Topical steroids can be used to enhance local treatment response for mild cGVHD. Consistent tapering protocols have yet to be established and are guided by the severity of GVHD and the response to treatment. Approximately 50% of patients will respond to initial therapy; the remaining patients will develop either steroid-refractory or steroid-dependent disease.³⁵ Steroid-refractory cGVHD is defined as having progression on prednisone 1 mg/kg/day for ≥7 days or having stable disease despite therapy with prednisone 0.5 mg/kg/day for ≥4 weeks. Steroid-dependent disease is defined as the inability to taper prednisone below 0.25 mg/kg/day after ≥2 unsuccessful attempts separated by ≥8 weeks.^{36, 37} Long-term therapy with corticosteroids is associated with multiple adverse events (AEs) (e.g., osteoporosis, myopathies, mood changes, weight gain, hypertension, and diabetes), which highlights the unmet need for more-efficacious, less-toxic, and better-directed therapies for cGVHD.

Treatment of Steroid-Refractory cGVHD (Federal Drug Administration [FDA] Approved) Ibrutinib.

Ibrutinib is the first FDA-approved agent for steroid-refractory cGVHD.³⁸ It is an irreversible dual inhibitor of both Tec family kinases, Bruton tyrosine kinase and IL-2–inducible T-cell kinase (Figure 2).³⁸ Antigen recognition by B-cell receptors results in activation of the Bruton tyrosine kinase signaling pathway, which leads to survival, proliferation, and migration of B-cells.³⁹ Additionally, stimulation of T-cell receptors results in a downstream signaling cascade that leads to T-cell activation, proliferation, and cytokine release. Thus, ibrutinib inhibits activation of B- and T-cells. The efficacy and safety of ibrutinib were initially evaluated in a phase II study (n=42).⁴⁰ Patients who received ibrutinib (420 mg dose) had a best overall response rate (ORR) of 67%. Of note, 71% of responders had a sustained response for >20 weeks. These responses were mainly partial responses (45%); the median time to response was 12.4 weeks (range, 4.1 to 42.1 weeks). High response rates were seen in patients with GVHD involvement of the skin (88%), mouth (88%), and GI tract (91%). Common AEs included fatigue, diarrhea, muscle spasms, and bruising (Table 1). Of importance, no major hemorrhage events were reported, and atrial fibrillation occurred infrequently. A 1-year follow-up study reported a similar ORR (69%), with higher rates of complete response (21% to 31%) than in the initial study and similar rates of AEs.⁴¹

Fig. 2: Mechanism of action of ibrutinib, ruxolitinib, and belumosudil in chronic graft-versus-host disease.

Ibrutinib inhibits Bruton tyrosine kinase–dependent and immune thrombocytopenia–dependent processes. Ruxolitinib inhibits Janusassociated kinase 1/2–dependent processes. Belumosudil inhibits the rho-associated coiled-coil–containing protein kinase 2–dependent pathway. α-SMA alpha smooth muscle actin, Ag antigen, APC antigen-presenting cell, BCR B-cell receptor, BEL belumosudil, BLNK B-cell linker protein, BTK Bruton tyrosine kinase, cGVHD chronic graft-versus-host disease, CTGF connective tissue growth factor, FDA Federal Drug Administration, GDP guanosine diphosphate, GEF guaninine nucleotide exchange factor, GTP guanosine triphosphate, IBR ibrutinib, ITK interleukin-2–inducible T-cell kinase, ITP immune thrombocytopenia, JAK Janus-associated kinase, LAT linker for the activation of T-cells, LcK lymphocyte-specific protein tyrosine kinase, LYN Lck/Yes novel tyrosine kinase, MRTF myocardin-related transcription factor, PDGFR-α platelet-derived growth factor receptor alpha, PLC phospholipase C, ROCK2 rhoassociated coiled-coil–containing protein kinase 2, RUX ruxolitinib, SLP-76 SH2-domain–containing leukocyte protein of 76kDa, STAT signal transducer and activator of transcription, SYK spleen tyrosine kinase, TCR T-cell receptor, Tfh T follicular helper, TGF-β tumor growth factor beta, Th17 T helper cell 17, Treg cell T regulatory cell, ZAP-70 zeta-chain–associated protein kinase 70.

Table 1.

FDA-approved agents for steroid-refractory chronic graft-versus-host disease

Drug	Mechanism of Action	Study	Enrollment	Median Time to Response	Treatment Response	Other Outcomes	FDA Indication	Dose	Drug/Drug Interactions	Toxicity
Ibrutinib (IMBRUVICA)38, 40	Bind to BTK active site, leading to inhibition of BTK enzymatic activity; results in downstream inhibition of B-cell antigen receptor and cytokine receptor pathways	Phase 1b/2	N=42 After ≥1 line of therapy	12 weeks	ORR: 67% CR: 9% PR: 19%	FFS: 51% (18 months) Median duration of treatment: 1.8 months	After failure of ≥1 lines of therapy	420 mg daily Available in 140-mg, 280-mg, and 420-mg tablets Take with or without food	CYP3A4 inhibitors (fluconazole, posaconazole, voriconazole, isavuconazole) Anticoagulants	Fatigue (57%) Bruising (40%) Diarrhea (36%) Thrombocytopenia (33%) Muscle spasms (29%) Stomatitis (29%) Nausea (26%) Hemorrhage (26%) Anemia (24%) Pneumonia (21%)
		Retrospective single center	N=53	NR	ORR: 12% CR: 4% PR: 8% SD: 64%	Median FFS: 4.5 months 2-year FFS: 9%
Ruxolitinib (JAKAFI)43, 45, 46	Inhibit JAK1 and JAK2, inhibiting recruitment of STATs to cytokine receptors	REACH3 Phase III	N=329 After ≥1 line of therapy	3 weeks	ORR: 49.7% CR: 6.7% PR: 43%	Median FFS: >18.6 months Median duration of treatment: 25.6 weeks	After failure of 1 or 2 lines of systemic therapy	10 mg twice daily Available in 5-mg and 10-mg tablets Take with or without food	CYP3A4 inhibitors (fluconazole, posaconazole, voriconazole, isavuconazole)	Hypercholesterolemia (88%) Anemia (82%) Thrombocytopenia (58%) Infection (45%) Viral infection (28%) Neutropenia (27%) CMV (5%−8%)
		Retrospective single center	N=48 After ≥1 line of therapy	2 months	ORR: 77% CR: 15%	Median duration of response: 11 months Median duration of treatment: 12 months
Belumosudil (REZUROCK)49, 52	Inhibits ROCK2 and ROCK1, regulates STAT3/STAT5 pathways and shifting Th17/Treg balance, inhibits aberrant profibrotic signaling	ROCKstar Phase II	N=132 After 2 to 5 lines of therapy	5 weeks	ORR: 74% (for belumosudil once daily) CR: 6% PR: 68%	FFS: 56% (12 months) Median duration of treatment: 10 months	After failure of ≥2 lines of systemic therapy	200 mg once daily Available in 200-mg tablets Take with food	CYP3A4 inducers Proton pump inhibitors Certain P-gp, OATP1B1, BCRP, and UGT1A1 substrates	Fatigue (38%) Diarrhea (33%) Nausea (31%) Cough (28%) Upper respiratory tract infection (27%) Dyspnea (25%) Headache (24%) Peripheral edema (23%) Vomiting (21%) Muscle spasms (20%)

BTK, Bruton tyrosine kinase; CMV, cytomegalovirus; CR complete response; FFS, failure-free survival; JAK, Janus-associated kinase; NR, no response; ORR, overall response rate; PR, partial response; ROCK, rho-associated, coiled-coil–containing protein kinase; SD, stable disease; STAT, signal transducer and activator of transcription; Th17, T-helper cell 17; Treg, regulatory T cell.

In a single-center retrospective study,⁴² 53 patients were treated with ibrutinib for steroid-refractory cGVHD (median follow-up, 26 months). In this study, 2-year failure-free survival was 9% (95% CI, 2.6% to 20%), and median failure-free survival was 4.5 months (95% CI, 2.8 to 7.1 months). In total, 12% of patients in this study had a complete or partial response, and most patients (64%) had stable disease. Ibrutinib was not associated with a reduction in corticosteroid dose and was associated with only a modest response in patients with steroid-refractory cGVHD.

Ruxolitinib.

Ruxolitinib is a potent and selective inhibitor of JAK 1 and 2 (Figure 2).⁴³ In the early development of GVHD, activation of the intracellular JAK 1/2 pathway leads to transcription of proinflammatory cytokines, mediation of inflammatory neutrophil migration, and upregulation of MHC class II expression.⁴⁴ Alloreactive T-cell infiltration into target organs is mediated by IFN-γ and the chemokine receptor CXCR3. By inhibition of the JAK/STAT pathway, IFN-γ signaling is prevented. Ruxolitinib is approved by the FDA for steroid-refractory cGVHD on the basis of the results of REACH3, a phase III randomized controlled trial.^43,45 This trial evaluated the efficacy and safety of ruxolitinib versus best available therapy in patients with steroid-refractory or steroid-dependent cGVHD.⁴⁵ The ORR at 24 weeks was higher in the ruxolitinib arm than in the best available therapy arm (50% vs. 26%; p≤0.001). Patients treated with ruxolitinib were approximately 3 times more likely to have a response; partial response was the most common response in both groups. Responses were seen in all involved organs, with high ORRs for the lower GI tract (53%), esophagus (50%), mouth (50%), skin (41%), and upper GI tract (40%). Many patients who crossed over from control therapy to ruxolitinib still had a response (69%), highlighting the efficacy of ruxolitinib in later stages of therapy. The most common AEs were infections and cytopenia; thrombocytopenia and neutropenia were the most prevalent grade ≥3 AEs (Table 1).

Several real-world studies evaluating the safety and efficacy of ruxolitinib in patients with steroid-refractory cGVHD have been reported.^46,47,48 A retrospective single-center study (n=48) observed a similar 1-year ORR of 77%.⁴⁶ In total, 15% of patients in this study had a complete response; the median time to response was 2 months (range, 0.5 to 8 months). The ORR was 77%, 45%, and 33% in patients with involvement of the skin, gut, and lung, respectively. Two-year overall survival was higher among patients with a response (88% vs. 49%; p=0.01). The results of this study support ruxolitinib as a steroid-sparing agent, as corticosteroid dose was decreased by ≥50% in half of patients, and 21% of patients discontinued corticosteroids. Rates of AEs were similar to those in REACH3.^{45, 46}

Belumosudil.

Belumosudil is a selective ROCK2 inhibitor (Figure 2).⁴⁹ Activation of ROCK2 results in upregulation of STAT3 phosphorylation and, subsequently, of Th17-specific transcription factors. Inhibition of ROCK2 allows for the downregulation of proinflammatory cytokines including IL-17 and IL-21 in T-cells.^49,50,51 This results in a shift to an increase in regulatory T-cells. Additionally, activation of ROCK2 results in the polymerization of globular actin to fibrous actin via profibrotic mediators (e.g., TGF-β and lysophosphatidic acid). The presence of fibrous actin leads to further expression of profibrotic genes (e.g., connective tissue growth factor, alpha smooth muscle actin), which then promotes the production of myofibroblasts and collagen, creating a profibrotic environment. In pre-clinical models, the inhibition of ROCK2 by belumosudil interferes with this profibrotic process in cGVHD.

A phase II, open-label, randomized, multicenter study evaluated belumosudil 200 mg once daily versus 200 mg twice daily (n=66 in each group) in patients with steroid-refractory cGVHD who had received 2 to 5 previous lines of therapy.⁵² After a median follow-up of 14 months, both groups had a high ORR—74% for once daily and 77% for twice daily—and responses were observed across all affected organs. Most responses (70%) were partial responses; few complete responses (2%) were observed. Patients who had previously received ruxolitinib had an ORR of 68%, and patients who had previously received ibrutinib had an ORR of 74%. The median time to response was 5 weeks (range, 4 to 66 weeks); among those with a response, the median duration of response was 54 weeks. Responses were durable: the response lasted ≥20 weeks in 60% of patients with a response. In this heavily pretreated population, belumosudil was associated with a clinically meaningful benefit in patients with ≥4 involved organs, in patients who were refractory to their last line of treatment, and in patients with severe cGVHD. Corticosteroid dose was decreased by a median of 45% from baseline in most patients. Among all study participants, 31% discontinued corticosteroid therapy, and 22% discontinued calcineurin inhibitor therapy. Belumosudil was well tolerated and was associated with a low discontinuation rate secondary to AEs (12%). The most common AEs of any grade were fatigue, diarrhea, nausea, cough, and upper respiratory tract infection (Table 1). Reactivation of cytomegalovirus infection was not observed.

Emerging Therapies for cGVHD

The treatment landscape for cGVHD has evolved with the advent of FDA-approved therapies.^40,45,52 However, there remains an unmet need to provide additional treatment options for patients who have a poor response, experience progression, or are intolerant to the current available therapies. Early-phase clinical trials evaluating newer agents that feature additional mechanisms and target additional pathways have been reported or are currently ongoing (Table 2).³⁶ Novel agents that are being investigated for the treatment of advanced cGVHD include: (i) baricitinib, a JAK 1/2 inhibitor, was evaluated in a phase I/II trial (n=24) and was associated with a preliminary, 6-month ORR of 79.2%, with responses seen in all organs except the lung; (ii) abatacept, a selective costimulation modulator that inhibits T-cell activation, was evaluated in a phase II study (n=36) and was associated with an ORR of 58% (all partial responses), with the most notable improvements in the lungs (33%), eyes (23%), mouth (21%), and joints (21%); (iii) ixazomib, a proteosome inhibitor, was evaluated in a phase II study (n=50) and was associated with a 6-month ORR of 40% and 12-month overall survival of 90%.^{53,54,55, 56} Axatilimab, an IgG4 monoclonal antibody, targets colony-stimulating factor–1 receptor that controls the survival and function of monocytes and macrophages.⁵⁷ The results of AGAVE-201, a phase II trial (n=241), showed a high ORR (74%) for axatilimab (0.3 mg/kg every 2 weeks) in 80 patients with steroid-refractory cGVHD for whom ≥2 lines of systemic therapy had failed.⁵⁸ How these novel therapies may be combined or sequenced to provide further benefit remains to be established.

Table 2.

Future therapies for chronic graft-versus-host disease

Agent	Mechanism/Target	Clinical Trial Identifier	Study Phase	No. of Patients	Line of Therapy	Dosing Schedule	Treatment Response	Toxicity
Baricitinib53, 56	JAK 1/2 Inhibitor	NCT02759731	I/II	24	Refractory after ≥1 line of therapy	Initial: 2 mg once dailya	6-month ORR: 79.2% (PR: 66.7%; MR: 12.5%)	Upper respiratory tract infection (33%) Hypophosphatemia (21%) Hypokalemia (17%) Hypertriglyceridemia (13%) Nausea (13%)
Abatacept54	Selective costimulation modulator inhibiting CD28	NCT01954979	II	36	Refractory after ≥1 line of therapy	10 mg/kg IV x 6 doses Doses 1–3: every 2 weeks Doses 4–6: every 4 weeks	5-month ORR: 58% (All PR)	Fatigue (9%) Neutropenia (6%) Headache (4%) Upper respiratory tract infection (3%)
Ixazomib55	20S proteasome inhibitor	NCT02513498	II	50	Refractory after ≥1 line of therapy	4 mg once weekly on days 1, 8, 15 of a 28-day cycle x 6 cycles	6-month ORR: 40% (All PR)	Nausea Fatigue Thrombocytopenia
Axatilimab57, 69	CSF-1R inhibitor	NCT04710576	II	241	Refractory after ≥2 lines of therapy	Cohort 1: 0.3 mg/kg IV every 2 weeks (maximum 2 years)	6-month ORR: 74%	Cohort 1 Fatigue (23%) Increased aspartate aminotransferase (14%) Increased lactate dehydrogenase (14%) Increased alanine aminotransferase (13%) Increased creatine phosphokinase (11%) Increased lipase (11%)
						Cohort 2: 1 mg/kg IV every 2 weeks (maximum 2 years)	6-month ORR: 67%
						Cohort 3: 3 mg/kg IV every 2 weeks (maximum 2 years)	6-month ORR: 50%

CSF-1R, colony-stimulating factor–1 receptor; IV, intravenous; JAK, Janus-associated kinase; MR, mixed response; ORR, overall response rate; PR, partial response; 1L, first line; 2L, second line.

^aAfter 12 weeks, maintain at 2 mg once daily if the patient has a complete response or increase to 4 mg once daily if the patient has a partial response. If progression of disease occurs within 12 weeks, increase to 4 mg once daily.

Barriers to Treatment of cGVHD

Once a treatment course has been formulated for a patient with cGVHD, the ability to appropriately manage polypharmacy and the drugs required for treatment should be emphasized. However, achieving this is frequently challenging.⁵⁹ In addition to the immunosuppressive treatments for cGVHD, additional supportive care agents, including agents for infection prophylaxis and agents to manage toxicities associated with immune suppression and/or cGVHD itself, are required.⁶⁰ This leads to significant increases in pill burden. A secondary analysis of the PROVIVO study, a multicenter cross-sectional analysis that examined patient-reported outcomes of long-term survivors after alloHCT, found a positive association between medication nonadherence and diagnosis of cGVHD. Eighty percent of patients with moderate to severe cGVHD reported some level of medication nonadherence.⁶¹ In addition to polypharmacy, other frequently associated barriers include tolerability and medication costs both in the United States and in other countries worldwide. One study identified cost >$30 for a medication as a reason for skipped doses or delayed refills.^{62, 63} Medication intolerability can contribute to medication nonadherence.⁶⁴ Weekly medication education and counseling sessions performed by a clinical pharmacist have been shown to improve adherence scores in transplant patients.⁶⁵ Furthermore, other barriers to treatment of cGVHD includes lack of access to cGVHD specialty care, patient education and counseling, and supportive measures.^{60, 63, 66, 67}

Discussion

cGVHD is a complex posttransplant complication that is associated with substantial morbidity and mortality. Early treatment should be implemented to prevent further progression, improve patient outcomes, and increase quality of life. A multimodal approach for the treatment of cGVHD includes local and systemic therapies in conjunction with organ-specific supportive care modalities. High-dose systemic corticosteroids remain the first line of therapy; however, approximately 50% of patients will require additional lines of therapy. Patients who develop steroid-refractory or steroid-dependent cGVHD can be treated with one of the current FDA-approved agents (ibrutinib, ruxolitinib, or belumosudil). The choice of a second-line agent may be based on FDA labeling, GVHD characteristics, provider experience, costs, and toxicity profile. Additionally, access to novel therapeutic agents for treatment of cGVHD may be limited outside of the United States. Ibrutinib and ruxolitinib are approved by the FDA for use after ≥1 systemic therapy fails. However, ruxolitinib may be favored over ibrutinib because of the faster median time to response, its steroid-sparing effect, and efficacy demonstrated in REACH3. Belumosudil is approved after failing ≥2 lines of systemic therapy and may be favored for patients who have lung involvement or advanced fibrosis. Additionally, belumosudil may be favored over ruxolitinib when there is a concern for cytopenia. Other agents are under investigation and may provide additional therapeutic options for patients who are intolerant or unresponsive to the currently available FDA-approved therapies. Evaluating newer agents that either have different mechanisms or target different pathways will help to improve treatment options for patients with steroid-refractory or steroid-dependent cGVHD.

An approach that features a multidisciplinary care team—consisting of physicians, clinical pharmacists, advanced practice providers, nursing staff, social workers and case managers, physical and occupational therapists, and specialized consult services—is strongly recommended. Referral to a specialized GVHD center can assist local and community clinical practices in the optimization of GVHD therapy and continuity of care. Patients with moderate to severe cGVHD frequently have multiorgan involvement and require specialized care, including dental, dermatology, nutrition, and ophthalmology. Patients may require treatment with several therapies to achieve a response, in addition to organ-specific supportive care therapies to improve quality of life and agents for infection prophylaxis. Toxicities from cGVHD-directed therapies are common and include impaired bone health, hyperglycemia, hypertension, and muscle atrophy. Because of the chronicity of the symptoms, efforts should be made to enhance quality of life, prevent further organ damage, and limit toxicities associated with treatment. Tools to measure symptoms (e.g., Lee Symptom Scale Score) and responses have been previously published.⁶⁸

Medication errors from nonadherence or polypharmacy can be minimized using a continuous multidisciplinary approach. Patient education is a critical step that should be performed at regular intervals to ensure patient understanding and compliance. Clinical pharmacists can be used for these education sessions, as they can assist with medication management, patient education, and counseling. Furthermore, medication nonadherence is commonly caused by several factors including poor access to cGVHD specialized care, high medication costs including countries outside of the United States, and poor drug tolerability. Ensuring that medications are available at affordable costs, that continuous symptom and tolerability assessments are performed, and that proper caregiver support is available are necessary to ensure treatment success and to improve patient outcomes.

With the advent of targeted therapies that have improved outcomes for patients, the treatment of cGVHD has evolved substantially during the last decade. With a continued emphasis on a multidisciplinary approach and the investigation of novel therapies, further advancements can be made for this unique and complex patient population.

Data Availability Statement:

Not applicable.