Graft Versus Host Disease for the General Oncologist

George Chen, MD

Roswell Park Cancer Institute

Elm and Carlton Streets

Buffalo, NY 14263

716 845 8722

George.chen@roswellpark.org

Abstract

Allogeneic hematopoietic cell transplant (alloHCT) can be a mysterious process for patients and general oncologists. Patients are referred to transplant centers that are sometimes far from their residences, travel there to receive therapy, and return with new immune systems and a new set of potentially lifethreatening complications of which they must be aware. Graft versus host disease (GvHD) is the most common complication of alloHCT. With the rising number of alloHCTs performed yearly for broader indications, general oncologists are increasingly likely to encounter GvHD. This article will review the pathophysiology of GvHD as well as general principles of treatment.

Since its first report in 1968 by Thomas and Ferrebee et al, hematopoietic cell transplantation (HCT) has evolved into a standard therapy used in the treatment of many hematologic and oncologic disorders.¹HCT can utilize autologous (self) or allogeneic (non-self) hematopoietic cells. The purpose of autologous HCT (autoHCT) is to rescue patients from the marrow ablative effects of high-dose chemotherapy. AutoHCT is used to treat malignancies such as germ cell tumors, selected cases of non-Hodgkin and Hodgkin lymphoma, and multiple myeloma, which have steeply positive dose versus response curves. In contrast, allogeneic HCT (alloHCT) is used to provide an immune effect against the underlying malignancy, as well as to restore hematopoiesis that has been destroyed by chemotherapy preparative and therapeutic regimens. Disorders for which alloHCT has been incorporated as a standard therapy include acute myeloid and lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative diseases, aplastic anemia, and certain inherited bone marrow disorders.

Graft versus host disease (GvHD) is the immunologic reaction of the donor’s cells (the graft) against the recipient’s body (the host). In 1966, RE Billingham succinctly postulated the necessary conditions for the development of GvHD as follows: 1) the recipient must be immunologically disparate from the donor; 2) the donor cells must be capable of recognizing these immunologic disparities; and 3) the donor cells must be able to persist and function in the recipient.²These postulates have been largely borne out: the incidence of GvHD is extremely rare to nonexistent in autologous HCT; the incidence is reduced when the donor graft has not completely replaced the recipient’s hematopoietic system and it coexists with residual recipient hematopoietic cells in a state of mixed donor chimerism³; and, finally, immunosuppressive combination therapies can prevent the development of GvHD.⁴

Approximately 7000 alloHCTs are performed annually in the United States. Fifty percent of these will develop some form of GvHD.⁵The incidence of GvHD is predicted to increase in the next several years due to the increased use of peripheral blood grafts as opposed to bone marrow grafts,⁶increasing donor and recipient age,⁵and the increased use of HLA-mismatched and haploidentical donors.⁷

Acute Graft Versus Host Disease

Graft versus host disease can be classified as acute or chronic. Classically, acute and chronic GvHD (aGvHD, cGvHD) have been defined based upon their onset before or after day 100, respectively. More recently, because of the increasing recognition that cGvHD is pathophysiologically distinct from aGvHD, the two have been differentiated on the basis of their presenting symptoms.⁸Acute GvHD is characterized by dermatitis, hepatitis, and colitis. It can also present with upper gastrointestinal symptoms of anorexia and nausea.⁹Therapy to control aGvHD occurs in 2 phases: prophylaxis and treatment. Without prophylaxis, all alloHCT patients will develop aGvHD.10 Prophylaxis of aGvHD utilizes a variety of strategies to suppress the activity of T cells, which are thought to be the primary drivers of aGvHD. Pharmacologic strategies use agents such as a calcineurin inhibitor and methotrexate. Prophylaxis with regimens such as tacrolimus (TAC)/methotrexate (MTX) and TAC/micro-dose MTX/mycophenolate mofetil (MMF) can prevent aGvHD in 50% to 65% of alloHCT recipients.^11-14Cellular strategies deplete T cells, either ex vivo or in vivo, such as with cyclophosphamide and antithymocyte globulin (ATG).^15-17

Clinical Pearls

• Chronic GvHD (cGvHD) symptoms of cutaneous sclerotic disease, eye and mouth dryness, gastrointestinal symptoms, and shortness of breath can present insidiously at any time after alloHCT. Community oncologists are the first line of detection and can greatly contribute to the well-being of their patients who have undergone alloHCT.
• The decision to treat cGvHD with systemic therapy must take into consideration the patient’s risk for disease relapse as well as tolerance of his/her cGvHD manifestations.
• Referral back to the transplant center is important for further discussion of diagnostic and therapeutic options.

Even with prophylaxis, 35% to 47% of alloHCT patients will develop aGvHD. Primary therapy for aGvHD is glucocorticoids. Methylprednisolone (or its equivalent) is typically initiated at the dose of 2 mg/kg/day. If the patient is receiving a calcineurin inhibitor, the dose is maximized to prevent further development of aGvHD. Improvement in symptoms will typically occur within 5 days. Once symptoms improve, the dose of glucocorticoids is gradually reduced by 20% to 25% every 3 to 4 days. Once the dose reaches 0.5 mg/kg, tapering usually slows to 10% decrements until the glucocorticoids are discontinued. Tapering of calcineurin inhibitors usually follows afterward.

Approximately 50% of patients will respond to primary therapy for aGvHD.^11,12,18,19The remainder progress to second-line therapies, such as ATG, rituximab, pentostatin, etanercept, tocilizumab, and alemtuzumab. There is no clearly superior second-line therapy and each successive agent begets a progressively lower response rate. Approximately 5% to 10% of patients undergoing alloHCT will die from complications of aGvHD. These complications are often related to uncontrolled infections exacerbated by the immunosuppression needed to treat aGvHD.

Chronic Graft Versus Host Disease

General oncologists are unlikely to administer aGvHD prophylaxis or treatment because aGvHD typically occurs in the immediate posttransplant period while the patient is under the active care of the transplant service. However, it is possible for general oncologists to encounter patients with aGvHD symptoms in the setting of additional therapy for relapsed disease after alloHCT. Usually, this would consist of chemotherapy or a donor lymphocyte infusion, which would be given after the initial transplant in order to treat recurrent disease, prevent relapse, or to enhance engraftment of donor hematopoietic cells. In this situation, prompt recognition of the classic triad with confirmatory biopsy and initiation of glucocorticoid therapy or referral back to the transplant center are important.In contrast to aGvHD, general oncologists are more likely to encounter cGvHD. After the infusion of the allogeneic donor graft, patients are closely followed by the transplant service for any potential complications, such as aGvHD, infection, and graft failure, for approximately 100 days. After this period and in the absence of ongoing complications, patients are referred back to the primary oncologist for shared follow-up. Patients often live far from the transplant center and present first to their primary local oncologist with late transplant- related complications. Also, because many of the presenting symptoms of cGvHD are not typically associated with oncologic diseases, primary oncologists may be the first to notice a change in recipients of alloHCT. In this setting, early detection of cGvHD manifestations can speed diagnosis and therapy of cGvHD and greatly contribute to the continued well-being of patients. In fact, a study of patients’ self-perceptions of their own well-being before and after effective cGvHD therapy indicated that they felt as well after successful therapy of cGvHD as if they had not developed cGvHD at all.²⁰This underscores the need to treat as well as discover new ways to treat cGvHD.

Chronic GvHD is characterized by immune dysfunction, glandular destruction, and multi-organ fibrosis. It typically manifests as skin, lung, eye, and mouth disease that is reminiscent of autoimmune disorders. Cutaneous disease is the most common manifestation and occurs in 75% of cGvHD. The skin can be hyperpigmented, lichenoid, or sclerodermatous, resulting in skin thickening and loss of elasticity.²¹Shoulder, wrist, and ankle range of motion is often decreased because of limitations imposed by sclerodermatous skin surrounding the joint, as well as fibrosis of the underlying soft tissue. The lungs can present with fibrosis and decreased compliance. The eyes and mouth are typically sensitive and dry with a gritty feeling similar to Sjögren’s syndrome. These manifestations can negatively impact the health of alloHCT survivors with marked discomfort, functional impairment, and pain.

Recipients of alloHCT will often imperceptibly develop the symptoms of cGvHD. Clues to suggest nascent cGvHD often relate to its sclerotic manifestations. Patients will often complain of increased joint stiffness but not necessarily decreased joint mobility. They may have more trouble than usual reaching overhead cabinets or putting on sweaters because of impaired shoulder range of motion. They may have trouble with fine work using their fingers, such as handling small and delicate objects like eyeglasses, due to sclerosis of the forearm, wrist tendons, and ligaments. Thickening of midsection skin is often seen. These patients may notice that they have trouble bending over to tie their shoelaces. Patients who play golf may notice that their swing is not as effective as it once was because they cannot rotate as well. They may feel that they have difficulty reaching behind them, such as while putting objects in their back pockets. Severe cases of sclerodermal disease located in the midsection will result in decreased appetite secondary to early satiety due to restriction of abdominal expansion in response to food. Patients with cGvHD of the lungs may notice increased shortness of breath with mild exertion. Recovery from pulmonary infections may be prolonged and colonization with multiresistant Pseudomonas may occur. Finally, patients may notice increased eye irritation as well as oral sensitivity to eating crunchy, salty, or spicy foods. They may subconsciously begin avoiding their favorite spicy foods.

The onset of cGvHD can be slow and gradual over months. Sometimes, cGvHD presents acutely over several days, such as during the tapering of immunosuppression, either given for treatment of preexisting GvHD or for prophylaxis of aGvHD, as well as 1 to 4 weeks after a viral infection. Intense sun exposure can also be followed by a flare of cGvHD.

TABLE 1. Commonly Used Second-Line Therapies for Glucocorticoid-Resistant cGvHD

Drug

Overall Responses

Type of Evidence

Proposed Mechanism/Comments

Systemic therapies

Alemtuzumab³⁷

7/10 (70%)

Phase I prospective study

Anti-CD52 antibody that results in T-cell depletion

ECP⁵⁰

43/71 (61%)

Retrospective study

ECP induces apoptosis of leukocytes, which induce a tolerogenic response when reinfused into the patient

Hydroxychloroquine³⁴

17/32 (53%)

Phase II prospective study

Inhibit binding of peptides to the MHC groove so that peptides cannot shuttle to the cell surface for presentation to T cells; in vitro synergism with cyclosporine and tacrolimus

Imatinib^32,51

6/15 (40%) -15/19 (79%)

Phase I prospective studies

Inhibition of platelet-derived growth factor and transforming growth factor-β signal transduction, which results in collagen deposition and fibrosis in mouse models of scleroderma

MMF^52-54

18/25 (72%) - 7/11 (64%)

Retrospective studies

Reversible inhibitor of inosine monophosphate dehydrogenase, which is the only pathway for purine salvage in lymphocytes

Pentostatin²⁹

32/58 (55%)

Phase II prospective study

Nucleoside analog that is an irreversible inhibitor of adenosine deaminase, which is essential to purine metabolism and highly active in lymphocytes and macrophages

Rituximab^31,55

14/20 (70%) -32/37(86%)

Phase I and II prospective studies

Anti-CD20 antibody depletes B cells that may play a contributory role for cGvHD pathogenesis

Sirolimus⁵⁶

22/35 (63%)

Phase II prospective study

Macrocyclic triene antibiotic with immunosuppressive properties; prevents T- and B-cell activation; can work synergistically with tacrolimus and mycophenolate mofetil

Approximately 50% of patients receiving alloHCT will develop some form of cGvHD.^22,23Acute GvHD is a major risk factor for later development of cGvHD; onethird of aGvHD patients will develop cGvHD.²⁴Chronic GvHD is a major complication of alloHCT and the most frequent cause of nonrelapse mortality in long-term survivors.^25,26Chronic GvHD is thought to arise from the reaction of donor T cells against the recipient’s body tissues, as suggested by decreased cGvHD incidence rates in studies of alloHCT using T-cell—depleted hematopoietic cell grafts.²⁷However, the contribution of other immune cells, such as B cells, NK cells, and dendritic cells, is increasingly recognized, as demonstrated by the use of therapeutic agents targeting these mechanisms.

Chronic GvHD therapy is directed toward correcting the immunologic dysfunction, either by suppressing or modulating the donor immune system, or toward palliation of cGvHD dermatologic, ocular, and oral manifestations. The choice to target the underlying immune dysfunction or the symptoms depends on the patient. The severity of cGvHD has been associated with prolonged overall survival probably due to decreased relapse, possibly from a concomitant graft-versusmalignancy effect.²⁶Any therapy for cGvHD, especially immunosuppressive ones such as glucocorticoids and calcineurin inhibitors, should consider the possible reduction of graft-versus-malignancy effects. Many patients are able to tolerate mild cGvHD symptoms, such as patches of lichenoid skin, or they are able to control the impact of these lesions with symptomatic therapies.

Summary

Acknowledgments

The primary therapy for cGvHD is glucocorticoids and a calcineurin inhibitor, such as tacrolimus.²⁸Therapeutic responses in cGvHD are much slower than in aGvHD and may require several weeks to months. Approximately 50% of patients will not respond and will require second-line therapy. At this time, there is no standard approach to glucocorticoid refractory cGvHD. Many phase I/II studies of secondary therapies for cGvHD have been performed. Commonly used secondary therapies include rituximab, imatinib, hydroxychloroquine, pentostatin, extracorporeal photopheresis (ECP), and sirolimus (Table 1).^29-36A phase I study of alemtuzumab in cGvHD has recently been published.³⁷Given the extensive experience with this agent, alemtuzumab is also expected to be increasingly used. The addition of hydroxychloroquine, ECP, and mycophenolate mofetil to standard systemic therapy with a calcineurin inhibitor and prednisone has undergone randomized phase II or phase III testing.^35,38,39No benefit was seen with hydroxychloroquine or mycophenolate mofetil, while a slight benefit was seen with ECP. These trials were performed in the setting of first-line therapy of cGvHD rather than as second-line therapy for steroid refractory disease, suggesting that while these agents may not necessarily add to first-line therapy, they may be beneficial in the subgroup of patients dependent on glucocorticoids. Other agents for which evidence for use exists but which are not frequently used include alefacept, clofazimine, etretinate, halofuginone, low-dose methotrexate, thalidomide, thoracoabdominal radiation, and tocilizumab.^40-49Symptoms for ocular cGvHD manifestations may be treated with plugging or cautery of the tear ducts, artificial tears, autologous serum eye drops, and special lenses for ocular cGvHD.Graft versus host disease is the most common complication of alloHCT. Graft versus host disease presents as an acute or chronic illness. General oncologists are more likely to encounter and diagnose cGvHD. A close working relationship between the transplant center and the referring general oncologist is essential in order to optimize the long-term care of alloHCT patients. Therapy of cGvHD should be individualized to the patient based upon the risk for relapse, the patient’s tolerance of cGvHD manifestations, and the pace at which manifestations progress. Primary therapy of cGvHD is a calcineurin inhibitor and glucocorticoids. Responses to therapy occur over 3 to 6 months. Commonly used secondary therapies include rituximab, imatinib, and hydroxychloroquine.The author thanks Philip McCarthy, MD, for reviewing this paper and for helpful discussion.

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